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We sought to replicate previous findings that low endogenous opioid (EO) function predicts greater morphine analgesia and extended these findings by examining whether circulating endocannabinoids and related lipids moderate EO-related predictive effects. Individuals with chronic low-back pain (n = 46) provided blood samples for endocannabinoid analyses, then underwent separate identical laboratory sessions under 3 drug conditions: saline placebo, intravenous (i.v.) naloxone (opioid antagonist; 12-mg total), and i.v. morphine (0.09-mg/kg total). During each session, participants rated low-back pain intensity, evoked heat pain intensity, and nonpain subjective effects 4 times in sequence after incremental drug dosing. Mean morphine effects (morphine-placebo difference) and opioid blockade effects (naloxone-placebo difference; to index EO function) for each primary outcome (low-back pain intensity, evoked heat pain intensity, and nonpain subjective effects) were derived by averaging across the 4 incremental doses. The association between EO function and morphine-induced back pain relief was significantly moderated by endocannabinoids [2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)]. Lower EO function predicted greater morphine analgesia only for those with relatively lower endocannabinoids. Endocannabinoids also significantly moderated EO effects on morphine-related changes in visual analog scale-evoked pain intensity (2-AG), drug liking (AEA and 2-AG), and desire to take again (AEA and 2-AG). In the absence of significant interactions, lower EO function predicted significantly greater morphine analgesia (as in past work) and euphoria. Results indicate that EO effects on analgesic and subjective responses to opioid medications are greatest when endocannabinoid levels are low. These findings may help guide development of mechanism-based predictors for personalized pain medicine algorithms.
Predictors of responsiveness to opioid analgesic medications are not well understood. This study tested whether individual differences in endogenous opioid (EO) function are associated with analgesic responsiveness to morphine. In randomized, counterbalanced order over 3 sessions, 45 chronic low back pain participants and 31 healthy controls received an opioid antagonist (8 mg naloxone), morphine (0.08 mg/kg), or placebo. Participants then engaged in 2 laboratory-evoked pain tasks (ischemic and thermal). Outcomes included pain threshold, pain tolerance, and pain ratings. Indexes of EO function and morphine analgesic responsiveness were derived for each measure as the difference in pain responses between the placebo condition and naloxone or morphine condition, respectively. For all 7 pain measures across the 2 laboratory pain tasks, greater EO function was associated with significantly lower morphine analgesic responsiveness (P<0.001-P=0.02). Morphine reduced pain responses of low EO individuals to levels similar to those of high EO individuals receiving placebo. Higher placebo condition-evoked pain sensitivity was associated with significantly greater morphine analgesic responsiveness for 5 of 7 pain measures (P<0.001-P=0.02). These latter associations were significantly mediated by EO function for 4 of these 5 pain outcomes (all P values<0.05). In the laboratory-evoked pain context, opioid analgesic medications may supplement inadequate EO analgesia, with little incremental benefit in those with preexisting high EO function. Implications for personalized medicine are discussed.
Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
Plasma levels of beta-endorphin (BE), an endogenous opioid analgesic, are often reported as they relate to acute and chronic pain outcomes. However, little is known about what resting plasma BE levels might reveal about functioning of the endogenous opioid antinociceptive system. This study directly examined associations between resting plasma BE and subsequent endogenous opioid analgesic responses to acute pain in 39 healthy controls and 37 individuals with chronic low back pain (LBP). Resting baseline levels of plasma BE were assessed. Next, participants received opioid blockade (8 mg naloxone i.v.) or placebo in a double-blind, randomized, crossover design. Participants then underwent two acute pain stimuli: finger pressure (FP) pain and ischaemic (ISC) forearm pain. Blockade effects (naloxone minus placebo pain ratings) were derived to index endogenous opioid analgesic function. In placebo condition analyses for both pain stimuli, higher resting BE levels were associated with subsequently greater reported pain intensity (p's < 0.05), with this effect occurring primarily in healthy controls (BE × Participant Type interactions, p's < 0.05). In blockade effect analyses across both pain tasks, higher resting plasma BE predicted less subsequent endogenous opioid analgesia (smaller blockade effects; p's < 0.05). For the ISC task, these links were significantly more prominent in LBP participants (BE × Participant Type Interactions, p's < 0.05). Results suggest that elevated resting plasma BE may be a potential biomarker for reduced endogenous opioid analgesic capacity, particularly among individuals with chronic pain. Potential clinical implications are discussed.
© 2011 European Federation of International Association for the Study of Pain Chapters.
OBJECTIVE - Elevated trait anger (TRANG; heightened propensity to experience anger) is associated with greater pain responsiveness, possibly via associations with deficient endogenous opioid analgesia. This study tested whether acute anger arousal moderates the impact of TRANG on endogenous opioid analgesia.
METHODS - Ninety-four chronic low back pain (LBP) participants and 85 healthy controls received opioid blockade (8 mg of naloxone) or placebo in a randomized, counterbalanced order in separate sessions. Participants were randomly assigned to undergo either a 5-minute anger recall interview (ARI) or a neutral control interview across both drug conditions. Immediately after the assigned interview, participants engaged sequentially in finger pressure and ischemic forearm pain tasks. Opioid blockade effects were derived (blockade minus placebo condition pain ratings) to index opioid antinociceptive function.
RESULTS - Placebo condition TRANG by interview interactions (p values < .05) indicated that TRANG was hyperalgesic only in the context of acute anger arousal (ARI condition; p values < .05). Blockade effect analyses suggested that these hyperalgesic effects were related to deficient opioid analgesia. Significant TRANG by interview interactions (p values < .05) for both pain tasks indicated that elevated TRANG was associated with smaller blockade effects (less endogenous opioid analgesia) only in the ARI condition (p values < .05). Results for ischemic task visual analog scale intensity blockade effects suggested that associations between TRANG and impaired opioid function were most evident in LBP participants when experiencing anger (type by interview by TRANG interaction; p < .05).
CONCLUSIONS - Results indicate that hyperalgesic effects of TRANG are most prominent when acute anger is aroused and suggest that endogenous opioid mechanisms contribute.
This case report presents data regarding endogenous opioid analgesia in a healthy female subject prior to developing chronic pain, and again 4 and 13 months following onset of chronic daily back pain. At each assessment period, the subject underwent identical protocols involving two sessions one week apart with randomized double-blind crossover administration of saline placebo and naloxone, an opioid antagonist. Each session included a 5-min anger recall interview, followed by finger pressure and ischemic acute pain tasks. Increases in acute pain ratings induced by opioid blockade were interpreted as reflecting endogenous opioid analgesia. When the subject was healthy and pain-free, naloxone produced a mean overall 16% decrease in pain ratings relative to placebo. However, 4 months after onset of chronic pain, a mean naloxone-induced increase of 22% in pain ratings over placebo was observed, consistent with presence of endogenous opioid analgesia. The mean magnitude of this opioid blockade effect for the finger pressure task exceeded the 99% confidence interval for the healthy control population based on a previous study using a similar opioid blockade protocol . At 13-month follow-up, naloxone produced a mean 45% decrease in acute pain ratings compared to placebo, arguing against presence of endogenous opioid analgesia. Although results must be interpreted cautiously, findings are consistent with the hypothesis that chronic pain may initially be associated with upregulation of endogenous opioid analgesic systems which then may become dysfunctional over time.
Copyright 2009 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
OBJECTIVE - Previous work suggests that elevated trait anger-out exacerbates pain responses in part through endogenous opioid dysfunction. The authors examined whether this opioid dysfunction affects not only perceived pain intensity, but also emotional responses to being hurt.
DESIGN - 79 chronic low back pain (LBP) patients and 46 healthy controls received opioid blockade (8 mg naloxone i.v.) and placebo in randomized, counterbalanced order in separate sessions. During each session, participants sequentially experienced finger pressure pain and ischemic forearm pain tasks, with emotional state assessed at baseline and postpain.
MAIN OUTCOME MEASURES - Blockade effects indexing opioid modulation of emotional reactivity were derived by subtracting placebo from blockade condition emotional reactivity.
RESULTS - Significant Participant Type x Anger-Out interactions on blockade effects indicated that in LBP participants but not in controls, greater anger-out was associated with deficient opioid modulation of anxiety, anger, and fear reactivity to noxious stimulation. Across participant types, greater anger-in was associated with impaired opioid modulation of anxiety and fear reactivity. Anger-in opioid effects were partially due to overlap with general negative affect.
CONCLUSIONS - Opioid dysfunction associated with trait anger-out may affect not only perceived pain intensity, but also pain-related suffering in individuals with chronic pain conditions. Implications for understanding the health effects of anger management styles are discussed.
Copyright (c) 2008 APA, all rights reserved.
A family history of chronic pain has previously been linked to increased incidence of spontaneous acute pain and risk for chronic pain. Mechanisms underlying these associations are unknown, although similar effects on both acute and chronic pain suggest that central endogenous analgesic system differences may be relevant. This study tested whether a positive parental chronic pain history (PH+) was associated with impaired endogenous opioid analgesic responses to acute pain. Seventy-three chronic low back pain patients (LBP) and 46 pain-free controls received opioid blockade (8mg naloxone i.v.) and placebo blockade (saline) in randomized, counterbalanced order in separate sessions. During each, subjects participated in a 1-min finger pressure pain task followed by an ischemic forearm pain task, providing pain intensity ratings during and immediately following each task. To assess opioid analgesic function, blockade effects were derived by subtracting placebo from blockade condition pain responses. Placebo condition analyses indicated that both PH+ subjects and LBP subjects reported greater acute pain sensitivity than respective comparison groups (p's<.05). Multivariate analyses indicated that, beyond any influence of current chronic pain status, PH+ subjects failed to exhibit any endogenous opioid analgesia to acute ischemic pain, whereas PH- subjects elicited effective opioid analgesia (p<.05). A significant multivariate PHxSubject Type interaction (p<.05) indicated that opioid analgesic impairments were most prominent in PH+ LBP subjects. Similar analyses for finger pressure pain blockade effects were nonsignificant (p>.10). The possible heritability of endogenous opioid analgesic dysfunction observed in individuals with a positive parental chronic pain history remains to be investigated.
Previous work has suggested that positive associations between trait anger (TRANG) and pain sensitivity are due to dysfunctional endogenous opioid analgesic systems. In this study, we examined whether TRANG is associated with impaired opioid modulation of blood pressure (BP) recovery. A total of 46 pain-free normotensive controls and 69 normotensive chronic low back pain (LBP) sufferers received opioid blockade (8 mg naloxone i.v.) or placebo in randomized, counterbalanced order in separate sessions. During each, participants underwent a 1-min finger pressure pain task followed by an ischemic forearm pain task. Opioid blockade impaired post-pain BP recovery in controls but not LBP participants (ps < .001). In controls, low TRANG was associated with blockade-induced recovery impairments, with no blockade effect in high TRANG participants. In LBP participants, blockade did not alter recovery regardless of TRANG (interaction ps < .05). Results support dysfunctional opioid modulation of BP recovery in healthy high TRANG controls and further suggest chronic pain-related impairments in opioid-mediated cardiovascular recovery.
OBJECTIVE - To test whether endogenous opioid antinociceptive system dysfunction evidenced in response to acute pain stimuli is associated with increased clinical pain intensity in chronic pain sufferers, and to determine whether this association is moderated by disability level.
DESIGN - A double-blind, placebo-controlled, randomized crossover design. Subjects underwent laboratory acute finger pressure pain stimulation and ischemic pain stimulation under placebo and under opioid blockade with naloxone. The primary independent measures, reflecting degree of endogenous opioid antinociception, were opioid Blockade Effects derived to reflect the change elicited by naloxone in pain intensity ratings for the acute pain tasks. High and Low Disability groups were derived based on Pain Disability Index scores to allow examination of the influence of disability level on the relationship between Blockade Effects and chronic pain intensity.
SUBJECTS - Twenty-eight chronic low back pain sufferers.
OUTCOME MEASURE - Seven-day diary ratings of overall chronic pain intensity based on McGill Pain Questionnaire-Short Form total scores.
RESULTS - Greater daily chronic pain intensity was associated with greater placebo acute pain sensitivity in the laboratory (P < 0.05). Positive Blockade Effects (ie, presence of opioid analgesia) were associated as expected with lower placebo-condition acute pain sensitivity in the laboratory (P < 0.05). In main effects analyses, Blockade Effects were not associated significantly with daily chronic pain intensity. This absence of overall main effects was accounted for by significant opposing interactions between disability level and Blockade Effects (P < 0.05). Negative Blockade Effects (ie, absence of endogenous opioid analgesia to acute pain) in the High Disability group were associated with greater daily chronic pain intensity, consistent with the hypothesized effects of chronic pain-related opioid dysfunction. In contrast, Positive Blockade Effects (ie, effective opioid analgesia to acute pain) were associated with higher daily chronic pain intensity in the Low Disability group.
CONCLUSIONS - These results suggest that endogenous opioid antinociceptive system dysfunction may contribute to elevated acute and chronic pain sensitivity among more disabled chronic pain patients. Among less disabled patients, chronic pain may serve as a primer producing up-regulated opioid antinociceptive responses to acute pain