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Opioid-induced hyperalgesia (OIH) occurs when opioids paradoxically enhance the pain they are prescribed to ameliorate. To address a lack of perioperative awareness, we present an educational review of clinically relevant aspects of the disorder. Although the mechanisms of OIH are thought to primarily involve medullary descending pathways, it is li...
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Citations
... This may have an impact on postoperative pain management [55], and the relationship appears to be dose-dependent [65]. When it comes to proven effects in the prevention and treatment of OIH and the development of tolerance to opioids, ketamine or magnesium sulfate (NMDA receptor antagonists), as well as alpha 2 agonists, often included in OFA protocols, are used [67][68][69][70]. OFA has a beneficial effect on reducing the doses of opioids used and, therefore, on the prevention of OIH and the development of tolerance to opioids. ...
Opioid-free anesthesia (OFA) is a heterogeneous group of general anesthesia techniques in which the intraoperative use of opioids is eliminated. This strategy aims to decrease the risk of complications and improve the patient’s safety and comfort. Such potential advantages are particularly beneficial for selected groups of patients, among them obese patients undergoing laparoscopic bariatric surgery. Opioids have been traditionally used as an element of balanced anesthesia, and replacing them requires using a combination of coanalgesics and various types of local and regional anesthesia, which also have their side effects, limitations, and potential disadvantages. Moreover, despite the growing amount of evidence, the empirical data on the superiority of OFA compared to standard anesthesia with multimodal analgesia are contradictory, and potential benefits in many studies are being questioned. Additionally, little is known about the long-term sequelae of such a strategy. Considering the above-mentioned issues, this study aims to present the potential benefits, risks, and difficulties of implementing OFA in bariatric surgery, considering the current state of knowledge and literature.
... 10,11 In an experimental human pain model, intravenous and sublingual buprenorphine had a lasting antihyperalgesic effect, 12 an effect likely mediated by antagonism at the κ-OR. 13 Buprenorphine is also a low-affinity agonist at the nociceptin opioid receptor (formerly known as opioid receptor-like 1 receptor), which blocks tolerance to analgesia, diminishes reward, and likely contributes to the relatively lower potential for abuse. 8,9,14,15 Buprenorphine has a high affinity, high potency, and slow dissociation rate at the µ-OR allowing for effective and long-lasting analgesia at microgram doses. ...
Due to the prevalence of chronic pain and high-impact chronic pain in the US, a significant percentage of the population is prescribed opioids for pain management. However, opioid use disorder is associated with reduced quality of life, along with fatal opioid overdoses, and is a significant burden on the US economy. Considering the clinical needs of patients with intractable chronic pain and the potential harms associated with prescribed and illicit opioids in our communities, having a deep understanding of current treatment options, supporting evidence, and clinical practice guidelines is essential for optimizing treatment selections. Buprenorphine is a Schedule III opioid with a unique mechanism of action, allowing effective and long-lasting analgesia at microgram doses with fewer negative side effects and adverse events, including respiratory depression, when compared with other immediate-release, long-acting, and extended-release prescription opioids. Due to its relatively lower risk for overdose and misuse, buprenorphine was recently added to the Clinical Practice Guideline for the Use of Opioids in the Management of Chronic Pain as a first-line treatment for chronic pain managed by opioids by the US Departments of Defense and Veterans Affairs, and the Department of Health and Human Services recommends that buprenorphine be made available for the treatment of chronic pain. In this narrative review, we discuss the different buprenorphine formulations, clinical efficacy, advantages for older adults and other special populations, clinical practice guideline recommendations, and payer considerations of buprenorphine and suggest that buprenorphine products approved for chronic pain should be considered as a first-line treatment for this indication.
... Additionally, OIH is caused by dysfunction of the nociceptive pathway down the spinal cord through the rostral ventral medulla. 2 Activating neurons that project from the periaqueductal gray (PAG) to the rostral ventromedial medulla (RVM) and subsequently to the spinal cord is a common classic circuit of pain downward the control route. [3][4][5] The medial prefrontal cortex (mPFC) is involved in pain perception and sensation. ...
Purpose
Functional connectivity between the prelimbic medial prefrontal cortex (PL-mPFC) and the core of the nucleus accumbens (NAc core) predicts pain chronification. Inhibiting the apoptosis of oligodendrocytes in the PL-mPFC prevents fentanyl-induced hyperalgesia in rats. However, the role of prefrontal cortex (PFC)-NAc projections in opioid-induced hyperalgesia (OIH) remains unclear. Herein, we explored the role of the PL-NAc core circuit in fentanyl-induced hyperalgesia.
Methods
An OIH rat model was established, and patch-clamp recording, immunofluorescence, optogenetics, and chemogenetic methods were employed for neuron excitability detection and nociceptive behavioral assessment.
Results
Our results showed decreased activity of the right PL-mPFC layer V output neurons in rats with OIH. Similarly, the excitability of the NAc core neurons receiving glutamatergic projections from the PL-mPFC decreased in OIH rats, observed by the light-evoked excitatory postsynaptic currents/light-excited inhibitory postsynaptic currents ratio (eEPSC/eIPSC ratio). Fentanyl-induced hyperalgesia was reversed by optogenetic activation of the PL-NAc core pathway, and chemogenetic suppression of this pathway induced hyperalgesia in control (saline-treated) rats. However, behavioral hyperalgesia was not aggravated by this chemogenetic suppression in OIH (fentanyl-treated) rats.
Conclusion
Our findings indicate that inactivation of the PL-NAc core pathway may be a cause of OIH and restoring the activity of this pathway may provide a strategy for OIH treatment.
... The need for epidemiological data on opioid-related alterations of pain perception and hyperalgesia in special populations has only recently been articulated [40]. Existing clinical knowledge of OIH is largely limited to the perioperative period. ...
The administration of opioids can be followed by enduring neuroplastic changes in the peripheral and central nervous systems. This remodeling can lead to opioid-induced hyperalgesia, causing an increased sensitivity to painful stimuli. The description of opioid-induced changes in the somatosensory system has seldom been described in the setting of opioid agonist therapy in the treatment of opioid use disorders, and the few existing reports provide no guidance with respect to the effect of varied doses or substances.
The aim of the present study was to assess alterations of pain pathways among patients receiving opioid agonist therapy and to elucidate the dose-response relationship.
This study was planned as cross-sectional in an outpatient clinic in Graz, Austria. Patients receiving opioid agonist therapy for opioid use disorders (including methadone, levomethadone, buprenorphine, and extended-release morphine) were asked to fill out a questionnaire, including the central sensitization inventory. A battery of somatosensory system assessments was then performed.
A total of 120 patients participated (85 men/35 women). The mean oral morphine milligram equivalent (MME) was 694 ± 249 mg/day. Our study found significant alterations in pain perception, conditioned pain modulation, and wind-up. We demonstrated a moderate dose-response relationship between high-dose opioids and markers of central sensitization.
The present trial demonstrates the clear effects of opioid agonist therapy on the somatosensory system. Both central sensitization and descending pain modulation are negatively affected by high doses of opioids and our data elucidate a moderate dose-response relationship for these phenomena.
... There are also some genetic causes being investigated, one being a polymorphism in the catecholamine breakdown enzyme (COMT) that results in errors in dopamine and noradrenaline metabolism, causing altered levels in response to neurotransmitter activation. 30,31 OIH poses a significant concern in people with previous opioid exposure. Several studies assessing pain sensitivity using cold pressor, electrical, and pressure pain modalities showed increased sensitivity to cold pressor pain in opioidaddicted patients using medications for OUD (MOUD) compared with controls. ...
The opioid epidemic in the United States has led to an increasing number of pregnant patients with opioid use disorder (OUD) presenting to obstetric units. Caring for this complex patient population requires an interdisciplinary approach involving obstetricians, anesthesiologists, addiction medicine physicians, psychiatrists, and social workers. The management of acute pain in the parturient with OUD can be challenging due to several factors, including respiratory depression, opioid tolerance, and opioid-induced hyperalgesia. Patients with a history of OUD can present in one of three categories: 1) those with untreated OUD; 2) those who are currently abstinent from opioids; 3) those being treated with medications to prevent withdrawal. A patient-centered, multimodal approach is essential for optimal peripartum pain relief and prevention of adverse maternal and neonatal outcomes. Medications for opioid use disorder (MOUD), previously referred to as medication-assisted therapy (MAT), include opioids like methadone, buprenorphine, and naltrexone. These are prescribed for pregnant patients with OUD, but appropriate dosing and administration of these medications are critical to avoid withdrawal in the mother. Non-opioid analgesics such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) can be used in a stepwise approach, and regional techniques like neuraxial anesthesia and truncal blocks offer opioid-sparing options. Other medications like ketamine, clonidine, dexmedetomidine, nitrous oxide, and gabapentinoids show promise for pain management but require further research. Overall, a comprehensive pain management strategy is essential to ensure the well-being of both the mother and the fetus in pregnant patients with OUD.
... To improve the comfort, care experience, and outcomes of patients with SUD, early and effective management of pain and withdrawal symptoms must be prioritized. Doing so is especially important given what is known about activation of the stress response system during withdrawal from illicit opioids, 18 opioid-induced hyperalgesia (i.e., heightened sensitivity to pain induced by chronic opioid use) in individuals with OUD and in the post-operative period, 19,20 and the strong link between perceived undertreated pain and/or withdrawal and self-discharges. This finding is particularly salient in hospitals in Philadelphia and other areas that have an increasingly volatile and dangerous drug supply 21,22 that confounds typical withdrawal management strategies. ...
Background:
Rates of hospitalization for injection drug use-associated infective endocarditis (IDU-IE) are increasing. Much is known about the poor outcomes of patients with IDU-IE; less is known about the patient experience during hospitalization.
Objective:
To explore the experience of being hospitalized for endocarditis among individuals who inject drugs, providing a foundation on which to develop strategies to improve care for these patients.
Design:
Qualitative interviews with hospitalized patients undergoing cardiothoracic surgery with a history of injection drug use between February 2021 and May 2022 at the Hospital of the University of Pennsylvania.
Participants:
Cardiothoracic surgery patients with a documented history of injection drug use and the ability to speak English were recruited during their hospital stay.
Approach:
Thematic analysis of interviews guided by phenomenology and harm reduction theory was used to identify recurrent themes. Interviews were digitally recorded and transcribed and analyzed using NVIVO software.
Key results:
Interviews from 13 participants resulted in four major themes around Hospital Experience: (1) Kindness as an Antidote to Dehumanizing Treatment; (2) Relationships with the Care Team; (3) Withdrawal and Pain Management; and (4) Anticipating and Experiencing the Transition out the Hospital. Participants recounted long histories of dehumanizing care during previous hospitalizations, noted the value of open, sincere, and non-judgmental communication with clinical teams, expressed overall satisfaction with the management of their symptoms during the current hospitalization, reported self-discharging during previous hospitalizations due to undertreated pain and withdrawal, and noted significant challenges around discharge planning and execution.
Conclusions:
Participants noted structural (e.g., discharge planning) and interpersonal (e.g., stigma from care team) barriers to quality hospital care. They also noted that expressions of kindness from hospital staff were meaningful and comforting. Patients with IDU-IE face multi-dimensional challenges in the hospital. Their perspectives can meaningfully inform programs and initiatives to improve their outcomes and support recovery.
... This paradoxically increased pain sensitivity could be duplicated not only in opioid addicts but also in healthy human volunteers [2][3][4][5][6][7][8]. There are probably numerous causes for OIH, even though it is generally believed that the brain or brainstem is where the pain processes begin before moving through the spinal cord to the portion of the body that hurts [9]. So, a better comprehension of the underlying mechanism of OIH is prerequired for solving this dilemma. ...
Opioids are often first-line analgesics in pain therapy. However, prolonged use of opioids causes paradoxical pain, termed “opioid-induced hyperalgesia (OIH).” The infralimbic medial prefrontal cortex (IL-mPFC) has been suggested to be critical in inflammatory and neuropathic pain processing through its dynamic output from layer V pyramidal neurons. Whether OIH condition induces excitability changes of these output neurons and what mechanisms underlie these changes remains elusive. Here, with combination of patch-clamp recording, immunohistochemistry, as well as optogenetics, we revealed that IL-mPFC layer V pyramidal neurons exhibited hyperexcitability together with higher input resistance. In line with this, optogenetic and chemogenetic activation of these neurons aggravates behavioral hyperalgesia in male OIH rats. Inhibition of these neurons alleviates hyperalgesia in male OIH rats but exerts an opposite effect in male control rats. Electrophysiological analysis of hyperpolarization-activated cation current (Ih) demonstrated that decreased Ih is a prerequisite for the hyperexcitability of IL-mPFC output neurons. This decreased Ih was accompanied by a decrease in HCN1, but not HCN2, immunolabeling, in these neurons. In contrast, the application of HCN channel blocker increased the hyperalgesia threshold of male OIH rats. Consequently, we identified an HCN-channel-dependent hyperexcitability of IL-mPFC output neurons, which governs the development and maintenance of OIH in male rats.
... Opioid induced analgesia occurs due to nociceptive sensitization resulting in patient becoming paradoxically more sensitive to certain painful stimuli. [37] ...
... Opioidų sukeltą hiperalgeziją (OIH) būtina skirti nuo abstinencijos ir opioidų tolerancijos. Šios būklės skiriasi savo klinikine išraiška, kuri atsispindi 1 paveiksle [6]. ...
... Klinikiniame tyrime, kuriame sveikiems asmenims skausmas sukeltas naudojant terminį dirgiklį, nustatyta, jog homozigotiniai katechol-Ometiltransferazės geno met (158) polimorfizmui asmenys jautė didesnę hiperalgeziją. Kitame tyrime pagrįsta, jog lėtinis opioidų vartojimas skausmo malšinimui, ypač parenteriniu būdu ar didelėmis dozėmis, gali sukelti hiperalgeziją, o papildomas šių medikamentų vartojimas priešoperaciniu metu poveikį sustiprina [6,7]. Pastebėtos ir specifinių opioidų, pavyzdžiui remifentanilio, sąsajos su analgezijos pasireiškimu, tačiau yra ir šiam teiginiui prieštaraujančių straipsnių, todėl reikia atlikti daugiau tyrimų [6]. ...
... Kitame tyrime pagrįsta, jog lėtinis opioidų vartojimas skausmo malšinimui, ypač parenteriniu būdu ar didelėmis dozėmis, gali sukelti hiperalgeziją, o papildomas šių medikamentų vartojimas priešoperaciniu metu poveikį sustiprina [6,7]. Pastebėtos ir specifinių opioidų, pavyzdžiui remifentanilio, sąsajos su analgezijos pasireiškimu, tačiau yra ir šiam teiginiui prieštaraujančių straipsnių, todėl reikia atlikti daugiau tyrimų [6]. ...
Opioidai – vieni dažniausiai stipraus skausmo malšinimui vartojamų medikamentų. Nepaisant stipraus analgezinio poveikio, ši medikamentų grupė sukelia ir šalutinių reiškinių, tokių kaip silpnumas, pykinimas ar vėmimas, haliucinacijos, priklausomybė ir hiperalgezija. Pastarosios būklės veikimo mechanizmas dar nėra iki galo suprantamas, tačiau manoma, jog jis susijęs su glutamato receptorių aktyvavimu ir glutamato nešiklių slopinimu. Siekiant išvengti opioidinės hiperalgezijos, svarbu suprasti skirtumus tarp šios būklės ir tolerancijos bei abstinencijos, šviesti visuomenę apie neigiamą opioidų poveikį, kai reikia, suteikti pagalbą ir rinktis kitus veiksmingus nuskausminimo metodus.
... Accumulating evidence suggests that the administration of opioid drugs leads not only to pain relief, but may also lead to a paradoxical sensitization of nociceptors (1,2). This phenomenon is referred to as OIH and presents a substantial medical problem. ...
Opioid-induced hyperalgesia (OIH) is a state of paradoxically enhanced pain transmission, termed nociceptive sensitization, described to occur in both humans and animals after repeated administration of opioid drugs, including rapidly acting remifentanil. However, molecular mechanisms of OIH remain understudied. In this issue of the JCI, Yan Jin and colleagues provided strong evidence that hyperexcitable thalamocortical networks drive remifentanil-induced hyperalgesia in a rodent model of postsurgical pain. Furthermore, the authors specifically identified an important role of the CaV3.1 isoform of low-voltage-activated or T-type calcium channels (T-channels) in this process. Further experiments are needed to determine whether thalamic T channels could serve as targets for the treatment of OIH.
