Does Naloxone Reinstate Secondary Hyperalgesia in Humans after Resolution of a Burn Injury? A Placebo-Controlled, Double-Blind, Randomized, Cross-Over Study

Pereira, Manuel P.; Werner, Mads U.; Ringsted, Thomas K.; Taylor, Bradley K.; Dahl, J. B.

doi:10.1371/journal.pone.0064608

Cited by 19 publications

(61 citation statements)

References 60 publications

(66 reference statements)

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“…In summary, LS represents a predisposition to relapse that may explain the episodic nature and vulnerability to stress that accompanies chronic pain syndromes in humans (Le Roy et al, 2011, Corder et al, 2013), and thus may reflect a critical mechanism responsible for the transition from acute to chronic pain (Rivat et al, 2007). However, LS has not been reported in humans (Pereira et al, 2013), and our understanding of mechanisms of CNS synaptic plasticity in LS is limited to an involvement of NMDAR. Although the cellular mechanisms underlying LS are now emerging (see below and Corder et al), its synaptic basis remains poorly understood and so this is the focus of intense ongoing investigations.…”

Section: Spinal Mechanisms Of Persistent Painmentioning

confidence: 99%

“…We recently reported that low dose naloxone (0.021 mg/kg, i.v. ), delivered following resolution of hyperalgesia after cutaneous heat injury, did not reinstate heat hyperalgesia (Pereira et al, 2013). Rather than limited tissue injury of the model or species differences, this negative result was likely due to insufficient blockade of endogenous opioid receptors, as higher doses of naloxone have been used to demonstrate reinstatement in humans (M.P.…”

Section: Conceptual Model Conclusion and Clinical Significancementioning

confidence: 99%

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Endogenous Analgesia, Dependence, and Latent Pain Sensitization

Taylor

Corder

2014

Current Topics in Behavioral Neurosciences

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Endogenous activation of μ-opioid receptors (MORs) provides relief from acute pain. Recent studies have established that tissue inflammation produces latent pain sensitization (LS) that is masked by spinal MOR signaling for months, even after complete recovery from injury and re-establishment of normal pain thresholds. Disruption with MOR inverse agonists reinstates pain and precipitates cellular, somatic and aversive signs of physical withdrawal; this phenomenon requires N-methyl-D-aspartate receptor-mediated activation of calcium-sensitive adenylyl cyclase type 1 (AC1). In this review, we present a new conceptual model of the transition from acute to chronic pain, based on the delicate balance between LS and endogenous analgesia that develops after painful tissue injury. First, injury activates pain pathways. Second, the spinal cord establishes MOR constitutive activity (MORCA) as it attempts to control pain. Third, over time, the body becomes dependent on MORCA, which paradoxically sensitizes pain pathways. Stress or injury escalates opposing inhibitory and excitatory influences on nociceptive processing as a pathological consequence of increased endogenous opioid tone. Pain begets MORCA begets pain vulnerability in a vicious cycle. The final result is a silent insidious state characterized by the escalation of two opposing excitatory and inhibitory influences on pain transmission: LS mediated by AC1 (which maintains accelerator), and pain inhibition mediated by MORCA (which maintains the brake). This raises the prospect that opposing homeostatic interactions between MORCA analgesia and latent NMDAR–AC1-mediated pain sensitization create a lasting vulnerability to develop chronic pain. Thus, chronic pain syndromes may result from a failure in constitutive signaling of spinal MORs and a loss of endogenous analgesic control. An overarching long-term therapeutic goal of future research is to alleviate chronic pain by either: a) facilitating endogenous opioid analgesia, thus restricting LS within a state of remission; or b) extinguishing LS altogether.

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Section: Spinal Mechanisms Of Persistent Painmentioning

confidence: 99%

Section: Conceptual Model Conclusion and Clinical Significancementioning

confidence: 99%

Endogenous Analgesia, Dependence, and Latent Pain Sensitization

Taylor

Corder

2014

Current Topics in Behavioral Neurosciences

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“…[13] The participants were instructed to use a hair trimmer in the assessment area 2 days before the study, to avoid any interference with the sensory assessments. In case of inadequate trimming, the investigator removed any hair in the assessment area using a surgical hair trimmer (Surgical Clipper 9681, 3M Healthcare, MN).…”

Section: Methodsmentioning

confidence: 99%

“…First , over the course of our previous study to back-translate the human thermal injury model to a rodent model, it was revealed that doses of 3.0 to 10.0 mg/kg of naloxone, delivered 21 days after heat injury to the skin of the plantar hindpaw, were required to precipitate reinstatement of hypersensitivity. [11] Second , in our previous human studies in the heat injury model, low-dose naloxone infusion (21 μg/kg) [13] did not reinstate secondary hyperalgesia, whereas high-dose naloxone infusion (2.0 mg/kg) did precipitate reinstatement in 4 out of 12 subjects. [14] …”

Section: Safety Issuesmentioning

confidence: 99%

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Effects of target-controlled infusion of high-dose naloxone on pain and hyperalgesia in a human thermal injury model

Springborg

Jensen

Taylor³

et al. 2016

Medicine

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Mu-opioid-receptor antagonists have been extensively studied in experimental research as pharmacological tools uncovering mechanisms of pain modulation by the endogenous opioid system. In rodents, administration of high doses of mu-opioid-receptor antagonists after the resolution of an inflammatory injury has demonstrated reinstatement of nociceptive hypersensitivity indicating unmasking of latent sensitization. In a recent human study, pain hypersensitivity assessed as secondary hyperalgesia area (SHA), was reinstated 7 days after a mild thermal injury, in 4 out of 12 subjects after a naloxone infusion.The aims of the present study are first, to replicate our previous findings in a larger-sized study; second, to examine if high sensitizers (subjects presenting with large SHA after a thermal injury) develop a higher degree of hypersensitivity after naloxone challenge than low sensitizers (subjects presenting with restricted SHA after a thermal injury); and third to examine a dose–response relationship between 3 stable naloxone concentrations controlled by target-controlled infusion, and the unmasking of latent sensitization.Healthy participants (n = 80) underwent a screening day (day 0) with induction of a thermal skin injury (47°C, 420 seconds, 12.5 cm2). Assessment of SHA was performed 1 and 2 hours after the injury. Using an enriched design, only participants belonging to the upper quartile of SHA (Q4, high sensitizers; n = 20) and the lower quartile of SHA (Q1, low sensitizers; n = 20) continued the study, comprising 4 consecutive days—days 1 to 4. Thermal skin injuries were repeated on day 1 and day 3, whereas day 2 and day 4 (7 days after day 1 and day 3, respectively) were target-controlled infusion days in which the subjects were randomly allocated to receive either naloxone (3.25 mg/kg, 4 mg/mL) or placebo (normal saline) intravenous. The primary outcome was SHA assessed by weighted-pin instrument (128 mN) 0, 1, 2, and 165 to 169 hours after the thermal injury (day 1–4). The secondary outcomes were pin-prick pain thresholds assessed by weighted-pin instrument (8–512 mN) at primary and secondary hyperalgesia areas (days 1–4).The naloxone-induced unmasking of latent sensitization is an interesting model for exploring the transition from acute to chronic pain. The results from the present study may provide valuable information regarding future research in persistent postsurgical pain states.

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Persistent Postsurgical Pain: Evidence from Breast Cancer Surgery, Groin Hernia Repair, and Lung Cancer Surgery

Werner

Bischoff

2014

Behavioral Neurobiology of Chronic Pain

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The prevalences of severe persistent postsurgical pain (PPP) following breast cancer surgery (BCS), groin hernia repair (GHR), and lung cancer surgery (LCS) are 13, 2, and 4-12 %, respectively. Estimates indicate that 80,000 patients each year in the U.S.A. are affected by severe pain and debilitating impairment in the aftermath of BCS, GHR, and LCS. Data across the three surgical procedures indicate a 35-65 % decrease in prevalence of PPP at 4-6 years follow-up. However, this is outweighed by late-onset PPP, which appears following a pain-free interval. The consequences of PPP include severe impairments of physical, psychological, and socioeconomic aspects of life. The pathophysiology underlying PPP consists of a continuing inflammatory response, a neuropathic component, and/or a late reinstatement of postsurgical inflammatory pain. While the sensory profiles of PPP-patients and pain-free controls are comparable with hypofunction on the surgical side, this seems to be accentuated in PPP-patients. In BCS-patients and GHR-patients, the sensory profiles indicate inflammatory and neuropathic components with contribution of central sensitization. A number of surgical factors including increased duration of surgery, repeat surgery, more invasive surgical techniques, and intraoperative nerve lesion have been associated with PPP. One of the most consistent predictive factors for PPP is high intensity acute postsurgical pain, but also psychological factors including anxiety, catastrophizing trait, depression, and psychological vulnerability have been identified as significant predictors of PPP. The quest to identify improved surgical and anesthesiological techniques to prevent severe pain and functional impairment in patients after surgery continues.

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Does Naloxone Reinstate Secondary Hyperalgesia in Humans after Resolution of a Burn Injury? A Placebo-Controlled, Double-Blind, Randomized, Cross-Over Study

Cited by 19 publications

References 60 publications

Endogenous Analgesia, Dependence, and Latent Pain Sensitization

Endogenous Analgesia, Dependence, and Latent Pain Sensitization

Effects of target-controlled infusion of high-dose naloxone on pain and hyperalgesia in a human thermal injury model

Persistent Postsurgical Pain: Evidence from Breast Cancer Surgery, Groin Hernia Repair, and Lung Cancer Surgery

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