scholarly journals High-dose naloxone: Effects by late administration on pain and hyperalgesia following a human heat injury model. A randomized, double-blind, placebo-controlled, crossover trial with an enriched enrollment design

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0242169
Author(s):  
Anders Deichmann Springborg ◽  
Elisabeth Kjær Jensen ◽  
Mads Kreilgaard ◽  
Morten Aagaard Petersen ◽  
Theodoros Papathanasiou ◽  
...  
Keyword(s):  
High Dose ◽  
Secondary Hyperalgesia ◽  
Post Injury ◽  
Double Blind ◽  
Consistent Finding ◽  
Heat Injury ◽  
Postsurgical Pain ◽  
Chronic Postsurgical Pain ◽  
Pain Sensitization ◽  
Present Trial

Severe chronic postsurgical pain has a prevalence of 4–10% in the surgical population. The underlying nociceptive mechanisms have not been well characterized. Following the late resolution phase of an inflammatory injury, high-dose μ-opioid-receptor inverse agonists reinstate hypersensitivity to nociceptive stimuli. This unmasking of latent pain sensitization has been a consistent finding in rodents while only observed in a limited number of human volunteers. Latent sensitization could be a potential triggering venue in chronic postsurgical pain. The objective of the present trial was in detail to examine the association between injury-induced secondary hyperalgesia and naloxone-induced unmasking of latent sensitization. Healthy volunteers (n = 80) received a cutaneous heat injury (47°C, 420 s, 12.5 cm2). Baseline secondary hyperalgesia areas were assessed 1 h post-injury. Utilizing an enriched enrollment design, subjects with a magnitude of secondary hyperalgesia areas in the upper quartile (‘high-sensitizers’ [n = 20]) and the lower quartile (‘low-sensitizers’ [n = 20]) were selected for further study. In four consecutive experimental sessions (Sessions 1 to 4), the subjects at two sessions (Sessions 1 and 3) received a cutaneous heat injury followed 168 h later (Sessions 2 and 4) by a three-step target-controlled intravenous infusion of naloxone (3.25 mg/kg), or normal saline. Assessments of secondary hyperalgesia areas were made immediately before and stepwise during the infusions. Simple univariate statistics revealed no significant differences in secondary hyperalgesia areas between naloxone and placebo treatments (P = 0.215), or between ‘high-sensitizers’ and ‘low-sensitizers’ (P = 0.757). In a mixed-effects model, secondary hyperalgesia areas were significantly larger following naloxone as compared to placebo for ‘high-sensitizers’ (P < 0.001), but not ‘low-sensitizers’ (P = 0.651). Although we could not unequivocally demonstrate naloxone-induced reinstatement of heat injury-induced hyperalgesia, further studies in clinical postsurgical pain models are warranted.

scholarly journals Transition from Acute to Chronic Pain: Evaluating Risk for Chronic Postsurgical Pain

2019 ◽  
Vol 5 (22;5) ◽  
pp. 479-488
Author(s):  
Jingping Wang
Keyword(s):  
Risk Factors ◽  
Chronic Pain ◽  
Predictive Models ◽  
Narrative Review ◽  
Current Understanding ◽  
Anesthetic Techniques ◽  
Postsurgical Pain ◽  
Chronic Postsurgical Pain ◽  
Pain Sensitization ◽  
Underlying Pathophysiology

Background: The pathophysiology of pain involves complex nervous system interactions after initial noxious stimuli. When stimuli persist, biochemical and structural changes occur in the nociceptive pathways of the central and peripheral nervous systems, leading to pain sensitization. Peripheral and central sensitization are key in the transition from acute to chronic pain. This development of chronic pain is particularly common following various surgical procedures, with many postsurgical patients experiencing persistent pain for significant periods. Chronic pain is a common and severe complication of surgery, and preventing its development is tantamount in improving patient outcomes. Objectives: To understand underlying pathophysiology of chronic postsurgical pain (CPSP) and the underlying risk factors predisposing the transition from acute to CPSP. To review our ability to identify patients at highest risk for the development CPSP. To identify evidence-based multimodal approaches that can aid in the prevention of CPSP. Study Design: Narrative review of peer-reviewed literature. Setting: Inpatient surgical centers. Methods: Medline and Cochrane databases were reviewed to identify publications relevant to CPSP pathophysiology, risk factors, predictive models, and prevention. Publications were selected based on author expertise to summarize our current understanding of CPSP. Results: This review presents our current understanding of CPSP in the following domains: underlying pathophysiology, predisposing risk factors, predictive models of CPSP, and preventative strategies. Each section provides a structured review of key evidence base to understand the complex topic of CPSP. Limitations: This narrative review is a nonsystematic review of relevant publications aimed at presenting succinct overview of CPSP. Conclusions: The incidence of CPSP can potentially be reduced through early identification of perioperative, genetic, physiologic, and psychologic factors. Models predicting the development of CPSP continue to improve and may help focus preventative efforts in patients at highest risk. There is a growing body of evidence supporting the use of multimodal analgesia and anesthetic techniques in the reducing rates of CPSP development. Key words: Acute pain, chronic postsurgical pain, pain sensitization, chronic pain prevention, regional anesthesia, pain adjuncts, neuraxial anesthesia, chronic pain risk factors

Prevention of Cisplatin-Induced Emesis by the Oral Neurokinin-1 Antagonist, MK-869, in Combination With Granisetron and Dexamethasone or With Dexamethasone Alone

2001 ◽  
Vol 19 (6) ◽  
pp. 1759-1767 ◽  
Author(s):  
Daniel Campos ◽  
Jose Rodrigues Pereira ◽  
Rick R. Reinhardt ◽  
Carlos Carracedo ◽  
Sergio Poli ◽  
...  
Keyword(s):  
High Dose ◽  
Delayed Emesis ◽  
Double Blind ◽  
Acute Emesis ◽  
Group Iii ◽  
Group I ◽  
Efficacy Parameter ◽  
Group Ii ◽  
Neurokinin 1 ◽  
Present Trial

PURPOSE: The NK1-receptor antagonist MK-869 (L-754,030) has demonstrated antiemetic activity in humans receiving chemotherapy. Objectives of the present trial included the first assessment of oral MK-869 plus dexamethasone compared with a 5HT3 antagonist plus dexamethasone for prevention of acute and delayed emesis after high-dose cisplatin. Furthermore, the study sought to confirm that addition of MK-869 to a 5HT3 antagonist plus dexamethasone was more effective than just the 5HT3 antagonist plus dexamethasone for prevention of acute and delayed emesis. METHODS: This multicenter, double-blind, parallel-group trial in 351 cisplatin-naïve patients evaluated prevention of acute (0 to 24 hours) and delayed emesis (primary efficacy parameter; days 2 to 5) after cisplatin (≥70 mg/m2). Patients were randomized to four groups (I to IV) (n = number randomized; number evaluable): granisetron (10 μg/kg intravenously) pre-cisplatin followed by placebo on days 2 to 5 (group I) (n = 90; 90); granisetron and MK-869 (400 mg PO [by mouth]) pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group II) (n = 86; 84); MK-869 (400 mg PO) the evening before and pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group III) (n = 89; 88); or MK-869 (400 mg PO) pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group IV) (n = 86; 84). All patients also received dexamethasone (20 mg PO) before cisplatin. Additional medication was available to treat emesis or nausea at any time. RESULTS: In the acute period, 57%, 80%, 46%, and 43% of patients were without emesis in groups I, II, III, and IV, respectively (P < .01 for group II v group I). In the delayed period, the proportion of patients without emesis in groups I, II, III, and IV was 29%, 63%, 51%, and 57%, respectively (P < .01 for groups II, III, and IV v group I). The distribution of nausea scores in the delayed period was lower when comparing group II with group I (P < .05 for days 1 to 5 and days 2 to 5). One serious adverse event (dizziness) was rated as possibly related to MK-869. CONCLUSION: Once daily oral administration of MK-869 was effective in reducing delayed emesis and nausea after high-dose cisplatin. However, the combination of the 5HT3 antagonist plus dexamethasone was numerically superior to MK-869 plus dexamethasone in reducing acute emesis. Confirming and extending previous findings, the triple combination of a 5HT3 antagonist, MK-869, and dexamethasone provided the best control of acute emesis.

Pharmacotherapy for the Prevention of Chronic Pain after Surgery in Adults: An Updated Systematic Review and Meta-analysis

2021 ◽  
Author(s):  
Meg E. Carley ◽  
Luis E. Chaparro ◽  
Manon Choinière ◽  
Henrik Kehlet ◽  
R. Andrew Moore ◽  
...  
Keyword(s):  
Systematic Review ◽  
Risk Ratio ◽  
Preoperative Pain ◽  
Double Blind ◽  
Postsurgical Pain ◽  
Pain Status ◽  
Chronic Postsurgical Pain ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Meta Analyses

Background Chronic postsurgical pain can severely impair patient health and quality of life. This systematic review update evaluated the effectiveness of systemic drugs to prevent chronic postsurgical pain. Methods The authors included double-blind, placebo-controlled, randomized controlled trials including adults that evaluated perioperative systemic drugs. Studies that evaluated same drug(s) administered similarly were pooled. The primary outcome was the proportion reporting any pain at 3 or more months postsurgery. Results The authors identified 70 new studies and 40 from 2013. Most evaluated ketamine, pregabalin, gabapentin, IV lidocaine, nonsteroidal anti-inflammatory drugs, and corticosteroids. Some meta-analyses showed statistically significant—but of unclear clinical relevance—reductions in chronic postsurgical pain prevalence after treatment with pregabalin, IV lidocaine, and nonsteroidal anti-inflammatory drugs. Meta-analyses with more than three studies and more than 500 participants showed no effect of ketamine on prevalence of any pain at 6 months when administered for 24 h or less (risk ratio, 0.62 [95% CI, 0.36 to 1.07]; prevalence, 0 to 88% ketamine; 0 to 94% placebo) or more than 24 h (risk ratio, 0.91 [95% CI, 0.74 to 1.12]; 6 to 71% ketamine; 5 to 78% placebo), no effect of pregabalin on prevalence of any pain at 3 months (risk ratio, 0.88 [95% CI, 0.70 to 1.10]; 4 to 88% pregabalin; 3 to 80% placebo) or 6 months (risk ratio, 0.78 [95% CI, 0.47 to 1.28]; 6 to 68% pregabalin; 4 to 69% placebo) when administered more than 24 h, and an effect of pregabalin on prevalence of moderate/severe pain at 3 months when administered more than 24 h (risk ratio, 0.47 [95% CI, 0.33 to 0.68]; 0 to 20% pregabalin; 4 to 34% placebo). However, the results should be interpreted with caution given small study sizes, variable surgical types, dosages, timing and method of outcome measurements in relation to the acute pain trajectory in question, and preoperative pain status. Conclusions Despite agreement that chronic postsurgical pain is an important topic, extremely little progress has been made since 2013, likely due to study designs being insufficient to address the complexities of this multifactorial problem. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Reduction in Pain Sensitivity from Pharmacological Elevation of Blood Pressure in Persons with Chronically Low Blood Pressure

2009 ◽  
Vol 23 (3) ◽  
pp. 104-112 ◽  
Author(s):  
Stefan Duschek ◽  
Heike Heiss ◽  
Boriana Buechner ◽  
Rainer Schandry
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Pain Sensitivity ◽  
Pain Threshold ◽  
Pain Perception ◽  
Drug Effects ◽  
Pressure Effects ◽  
Double Blind ◽  
Low Blood Pressure ◽  
Present Trial

Recent studies have revealed evidence for increased pain sensitivity in individuals with chronically low blood pressure. The present trial explored whether pain sensitivity can be reduced by pharmacological elevation of blood pressure. Effects of the sympathomimetic midodrine on threshold and tolerance to heat pain were examined in 52 hypotensive persons (mean blood pressure 96/61 mmHg) based on a randomized, placebo-controlled, double-blind design. Heat stimuli were applied to the forearm via a contact thermode. Confounding of drug effects on pain perception with changes in skin temperature, temperature sensitivity, and mood were statistically controlled for. Compared to placebo, higher pain threshold and tolerance, increased blood pressure, as well as reduced heart rate were observed under the sympathomimetic condition. Increases in systolic blood pressure between points of measurement correlated positively with increases in pain threshold and tolerance, and decreases in heart rate were associated with increases in pain threshold. The findings underline the causal role of hypotension in the augmented pain sensitivity related to this condition. Pain reduction as a function of heart rate decrease suggests involvement of a baroreceptor-related mechanism in the pain attrition. The increased proneness of persons with chronic hypotension toward clinical pain is discussed.

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