Pain Response to Open Label Placebo in Induced Acute Pain in Healthy Adult Males.

BACKGROUND: Open label placebos with patient education are effective in reducing chronic pain, and recent studies on their effect on pain have established interest in this field. Nevertheless, data on their effect on acute pain are scarce, and on hyperalgesia and allodynia, absent. This study assessed the effect of open label placebos on acute pain in healthy adult males and the influence of placebo education. METHODS: Thirty-two healthy males were included in this prospective, randomized, assessor-blinded crossover, single-center study assessing pain intensities (via numeric rating scale), area of hyperalgesia (von Frey filament), and allodynia (dry cotton swab) in a pain model utilizing intracutaneous electrical stimulation. The authors compared the effect of intravenous open label placebo on pain compared to no treatment. The authors further examined the effect of placebo on hyperalgesia and allodynia, and the influence of education (short vs. detailed) before placebo application. Saliva cortisol concentrations were also measured. RESULTS: Pain ratings (median, first to third quartile) were 21% lower during placebo treatment compared to no treatment, 4.0 (3.2 to 4.9) versus 5.1 (4.7 to 5.4), respectively (P = 0.001). The areas of hyperalgesia and allodynia were lower during placebo treatment compared to no treatment (hyperalgesia, 30 cm [17 to 47] vs. 55 cm [42 to 68], P = 0.003; allodynia, 24 cm [11 to 39] vs. 45 cm [31 to 62], P = 0.007). This corresponds to reductions of 47%. The extent of placebo education had no effect on pain. Saliva cortisol decreased significantly over time and was under the limit of detectability in the majority of participants in postbaseline measurements in both treatment branches. Baseline cortisol was not associated with the placebo effect or strength applied of current to reach defined pain ratings. CONCLUSIONS: Open label placebos might play a role in multimodal analgesic concepts.

A Contextual Analysis to Explore Barriers and Facilitators of Pain Management in Swiss Nursing Homes.

PURPOSE: As part of a contextual analysis, this study aimed to generate a comprehensive understanding of barriers and facilitators to pain management in nursing homes to identify potential leverage points for future implementation studies. DESIGN: An explanatory sequential mixed-methods study embedded in a cross-sectional study in 20 Swiss nursing homes (data collection: July-December 2016). METHODS: Quantitative data were collected via care worker questionnaire surveys comprising 20 items assessing perceptions of barriers to pain management. Descriptive statistics were computed. In the subsequent qualitative strand we conducted four focus group discussions with care workers (registered nurses, licensed practical nurses, and nursing aides) using a knowledge-mapping approach. Findings of both strands were merged and mapped onto domains of the Capability, Opportunity, and Motivation determine Behavior (COM-B) system, a model for behavior, to identify determinants for behavior change. FINDINGS: Data from 343 completed care worker surveys (response rate 67.3%) and four focus groups with care workers were analyzed. Items rated most problematic were as follows: lack of availability of nonpharmacological treatment (60.9%), lack of application of nonpharmacological treatment (53.6%), reluctance of residents to report pain (51.1%), and lack of time for a comprehensive pain assessment (50.5%). Focus groups partly corroborated quantitative findings and complemented them with facilitators, such as close collaboration with physicians and further barriers (e.g., organizational factors such as high turnover and a lack of established routines in pain management). CONCLUSIONS: Our approach using a behavioral model highlighted a need for implementation strategies that improve pain management knowledge and focus on motivational aspects to establish new routines and habits related to pain management among care workers. CLINICAL RELEVANCE: Our findings suggest that future approaches to improve pain management in nursing homes should go beyond provision of education and training. To establish new practices or adapt existing ones, a more complex approach (e.g., introduction of external or internal facilitators) is necessary to influence motivation and ultimately change behavior.

[Opioid crisis: What now? A pain specialist's point of view]. / Die Opioid Krise ­ was nun?

Opioid crisis: What now? A pain specialist's point of view Abstract. In acute pain, opioids in combination with co-analgesics can be useful and indicated. It is important to evaluate and to treat every single patient individually. Therefore, experienced patient guidance is crucial in pain treatment to reduce the risk of side effects and inappropriate long-term opioid use. The indication and doses for opioids need continuous re-evaluation. Ineffective treatments with opioids have to be tapered. Furthermore, opioid prescription should always be limited in time with a plan to taper it to prevent misuse or even addiction. Alternative medical and non-medical treatment options are important as well. The following text gives advice on how to approach a patient with pain and contains a manual on how to handle opioids in different settings.

Association between intra-operative fentanyl dosing and postoperative nausea/vomiting and pain: A prospective cohort study.

BACKGROUND: Postoperative nausea and/or vomiting (PONV) is one of the anaesthesia-related effects most dreaded by patients and may delay hospital discharge. Although scores and risk factors are established, many were developed before contemporary anaesthesia regimens and without focussing on modifiable anaesthesia-related variables. OBJECTIVE: To examine whether, in association with a contemporary anaesthesia regimen, there is an association between intra-operative fentanyl dose and PONV, and, second, postoperative pain within the first 24 h. DESIGN: Prospective, observational cohort. SETTING: Single-centre university hospital. PATIENTS: Inclusion criteria were opioid-naive patients without chronic pain and with a simplified Apfel score at least 2 undergoing abdominal, gynaecological or otorhinolaryngological inpatient surgery. INTERVENTION: None. MAIN OUTCOME MEASURE: With logistic regression, we examined three models of increasing complexity exploring the relationship between PONV and fentanyl dosing: Model 1, simplified Apfel score + intra-operative fentanyl; Model 2, Model 1 + pre-emptive antiemetic prophylaxis; Model 3, Model 2 + postoperative morphine. Model 1 was the primary analysis. Second, we explored whether or not postoperative pain scores were associated with intra-operative fentanyl dosing. RESULTS: From the 363 patients, 163 (45%) experienced PONV, despite the use of total intravenous anaesthesia with propofol in more than 80% of the cohort, and some 66% of patients receiving additional antiemetic agents. After adjusting for the simplified Apfel score, higher intra-operative fentanyl dose was associated with PONV: odds ratio per µg h, 1.006 [95% confidence interval (CI) 1.002 to 1.010]. Including intra-operative fentanyl in the simplified Apfel score also increased the area under the receiver operator characteristics curve [0.601 (95% CI 0.555 to 0.662) vs. 0.651 (95% CI 0.594 to 0.707); P = 0.016]. Finally, a higher intra-operative fentanyl dose was associated with higher 24 h pain scores (P = 0.001) and a trend towards higher 24 h morphine requirements (P = 0.055). CONCLUSION: Even when using propofol and antiemetic agents, PONV within the first 24 h remained higher than expected. Intra-operative fentanyl, a modifiable risk factor, is associated with the incidence of PONV and postoperative pain. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03201315.

A theory-based hybrid II implementation intervention to improve pain management in Swiss nursing homes: A mixed-methods study protocol.

AIM: To present a protocol for evaluating an implementation intervention to improve pain management in nursing homes by addressing behaviour change of the care workers. BACKGROUND: Pain management in nursing homes often is inadequate despite the availability of evidence-based pain management guidelines. Barriers to pain management in nursing homes occur on several levels including lack of knowledge and negative beliefs towards pain of care workers. A comprehensive approach incorporating contextual and behavioural factors is needed to sustainably improve pain management practice. DESIGN: A hybrid type II effectiveness-implementation design comprising an incomplete non-randomized stepped-wedge design and concurrent focus groups is proposed. METHODS: A convenience sample of six nursing homes will be included. Implementation of a facility pain management policy will be facilitated by introduction of a facility pain champion and training of all care workers in pain assessment and management. Quantitative outcomes assessed at baseline, after 3 and 6 months include self-efficacy in pain management and attitudes to pain of care workers and functional interference from pain and pain intensity in residents. Feasibility and acceptability of the intervention and implementation strategies and potential barriers to implementation will be explored in focus groups and interviews. (Protocol approved in October 2017). CONCLUSION: The proposed intervention implementation has been developed in a participatory approach involving relevant stakeholders. To further improve the contextual fit, development of implementation strategies was guided by the consolidated framework of implementation research. Findings of this research are expected to inform adaptions to the implementation of the intervention. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT03471390.

Time course of copeptin during a model of experimental pain and hyperalgesia: A randomised volunteer crossover trial.

BACKGROUND: A reliable biomarker for quantifying pain or hyperalgesia has yet to be found. A surrogate marker of arginine vasopressin, copeptin, is elevated in a number of states of physiological and psychological stress and may have a role in quantifying pain and/or hyperalgesia. OBJECTIVES: To evaluate copeptin as a biomarker for pain or hyperalgesia developing after 120 min of sustained electrical stimulation. DESIGN: Secondary analysis of a randomised, double-blinded, crossover trial. SETTING: Single, tertiary university hospital from September 2014 to January 2015. PARTICIPANTS: A total of 16 healthy, opioid-naïve white men with no confounding medication or history of pain. INTERVENTIONS: Copeptin and cortisol were measured five times during an established model of transdermal electrical stimulation designed to assess pain and hyperalgesia. MAIN OUTCOME MEASURES: The primary outcome was the change in copeptin concentration after 120 min of sustained electrical stimulation. Secondary outcomes were copeptin and cortisol concentrations after a subsequent period of rest and analyses of copeptin and cortisol concentrations were made in high-dose and low-dose fentanyl groups separately. RESULTS: Total copeptin concentrations were not significantly elevated after 120 min [9.15 pmol l (interquartile ranges (IQR), 3.45 to 35.45 pmol l); P = 0.150] compared with baseline [6.15 pmol l (IQR, 3.60 to 10.62 pmol l)]. In the high-dose fentanyl group, there was a significant increase in copeptin within individuals [P = 0.001; median, 37.9 pmol l (IQR, 8.1 to 62 pmol l)] after 120 min, and in the low-dose fentanyl group a significant decrease in copeptin concentrations within individuals [P = 0.006; median, 4.7 pmol l (IQR, 3.13 to 9.35 pmol l)]. No correlation between copeptin concentration and either the area under the pain curve or area under the hyperalgesia curve could be found, indicating that the observed differences may be due to other fentanyl-mediated effects. CONCLUSION: Copeptin concentrations do not appear to be associated directly with pain and hyperalgesia. Instead, some fentanyl-mediated effect or effects appear to have greatly increased copeptin concentrations from baseline to 120 min. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02252458.

Does Fentanyl Lead to Opioid-induced Hyperalgesia in Healthy Volunteers?: A Double-blind, Randomized, Crossover Trial.

BACKGROUND: Although opioids in general and remifentanil in particular have been shown to induce hyperalgesia, data regarding fentanyl are scarce. Thus, the authors investigated the effect of fentanyl dosing on pain perception and central sensitization in healthy volunteers using established pain models. METHODS: Twenty-one healthy, male volunteers were included in this randomized, double-blind, crossover study and received either intravenous low-dose (1 µg/kg) or high-dose (10 µg/kg) fentanyl. Pain intensities and hyperalgesia were assessed by intracutaneous electrical stimulation, and cold pressor pain was used as an additional measure of acute pain. The primary outcome was hyperalgesia from 4.5 to 6.5 h after fentanyl administration. RESULTS: A higher dose of fentanyl led to significantly decreased pain scores as measured by the numeric rating scale (0.83 units lower [95% CI, 0.63 to 1.02]; P < 0.001) but increased areas of hyperalgesia (+30.5% [95% CI, 16.6 to 44.4%]; P < 0.001) from 4.5 to 6.5 h after fentanyl administration. Allodynia did not differ between groups (+4.0% [95% CI, -15.4 to 23.5%]; P = 0.682).The high dose also led to both increased cold pressor pain threshold (+43.0% [95% CI, 29.7 to 56.3%]; P < 0.001) and tolerance (+32.5% [95% CI, 21.7 to 43.4%]; P < 0.001) at 4.5 to 6.5h. In the high-dose group, 19 volunteers (90%) required reminders to breathe, 8 (38%) required supplemental oxygen, and 12 (57%) experienced nausea. CONCLUSIONS: A higher dose of fentanyl increased hyperalgesia from 4.5 to 6.5 h in healthy volunteers while simultaneously decreasing pain scores.

Correlation of (99m) Tc-DPD SPECT/CT Scan Findings and Diagnostic Blockades of Lumbar Medial Branches in Patients with Unspecific Low Back Pain in a Randomized-Controlled Trial.

OBJECTIVE: Zygapophyseal joints are the origin of pain in up to 30% of those with unspecific chronic low back pain. Until recently, no reliable clinical tests have been found to identify the patients who would benefit from denervation of the zygapophyseal joints by medial branch blockades. DESIGN: We performed a prospective randomized placebo-controlled trial to evaluate the value of high-resolution single-photon emission computed tomography (SPECT)/computed tomography (CT) of the lumbar spine prior to any diagnostic infiltration of the medial branches. METHODS: Patients with suspected zygapophyseal joint-related pain were included in the study. After obtaining a SPECT/CT scan of the lumbar spine a set of infiltrations of the medial branches was done with local anesthetics and placebo on different days. Patients and anesthetists were blinded to the results of SPECT/CT and to the infiltrated agents. RESULTS: In a total of 29 study patients, 7 had positive and 22 negative infiltration tests, and 9 had positive and 20 negative SPECT/CT findings. Sensitivity of SPECT/CT for a positive response after diagnostic infiltration was 0.57 (95% confidence interval [CI] 0.18-0.90); specificity was 0.77 (CI 95% 0.55-0.92); odds ratio was 4.53 (CI 95% 0.75-27.40); and diagnostic accuracy was 0.72. CONCLUSION: Compared with diagnostic infiltrations SPECT/CT scans showed only a moderate sensitivity and specificity and, therefore, may not be recommended as a first line diagnostic tool prior to diagnostic infiltrations.

Boosting open-label placebo effects in acute induced pain in healthy adults (BOLPAP-study): study protocol of a randomized controlled trial.

Introduction: Pain is a highly prevalent symptom in the hospital setting, but treatment options remain limited. Harnessing the placebo effect in an ethical manner could provide a new possibility to reduce pain in clinical practice. So called open-label placebos (OLP) have been shown to elicit significant effects in reducing acute pain. But, before implementation, more knowledge concerning the properties of OLPs is needed. This study aims to assess the duration of analgesic effects from OLP and to determine the possibility of boosting such effects. Methods and analysis: This is the protocol of an ongoing (first patient enrolled in March 2023) single-site randomized trial investigating OLPs in two parts (i.e., substudies). In both parts, pain will be induced in healthy adults using an intradermal electrical stimulation model. Participants in Part 1 will have two study visits: An interventional visit with one OLP injection accompanied by an evidence-based treatment rationale and a control visit with no treatment. For Part 2, participants will be randomized into three groups: (1) A fixed-time "Booster" group including one single repetition of the OLP injection at a fixed time point, (2) an on-demand "Booster" group including one single repetition of the OLP injection on-demand, and (3) a control group who will receive just one OLP injection. Differences in pain ratings over time (using the Numeric Rating Scale) will be analyzed with several two-sample t-tests. The time point for a fixed-time "Booster" in Part 2 will be derived from Part 1 with additional statistical tools such as a broken-stick mixed-effect model. Discussion: This study aims to further characterize the analgesic effects of OLPs. In doing so, it will provide valuable information needed for later implementation of OLPs in clinical practice, where they could play a role in multimodal analgesic concepts. Ethics and dissemination: The "Ethikkommission Nordwest- und Zentralschweiz" (BASEC 2023-00296) approved the study protocol. Results of the analysis will be submitted for publication in a peer-reviewed journal. Clinical Trial Registration: This study is registered at ClinicalTrials.gov (NCT05819476) and is listed in the Swiss National Registry at kofam.ch (SNCTP000005470).

Successful treatment of post-dural-puncture headache with surgical dura repair two years after spinal anesthesia.

BACKGROUND: Post-dural-puncture headache (PDPH) can be a highly disturbing complication of elective spinal anesthesia. The incidence of PDPH when small needles are used is estimated to be 0%-14.5%. PDPH usually resolves spontaneously within a few days, but there are rare cases that persist in spite of conventional and epidural blood patch therapy. CASE: A 59-year-old man suffered from persistent postural headache for more than two years after an otherwise uneventful spinal anesthesia. Conventional and minimally invasive treatments were unsuccessful. INTERVENTION/OUTCOME: A neurosurgical procedure was performed, during which a dural leak was identified and repaired. The patient was immediately pain free after surgery and has remained so for the duration of follow-up (more than one year).

Simultaneous application of lidocaine and ketamine during ambulatory infusion therapy: a retrospective analysis.

Background: Infusions with lidocaine or ketamine have been separately established in the treatment of chronic pain. This study aims to retrospectively evaluate the effect of combined infusions of lidocaine and ketamine. Materials & methods: Patient records were screened for receipt of combined ambulatory infusions of lidocaine and ketamine from 2012 through 2021. A scoring system was designed to assess pain response retrospectively. Results: A total of 319 patients were included. Median pain reduction in days was 10.00 (interquartile range: 13.25). Side effects were limited to the acute phase of infusions. A total of 41.4% of patients who received concomitant pain medication reported a dose reduction. Conclusion: Our data support combined infusions as a safe therapy option, with good short-, medium- and long-term reductions in pain and great heterogeneity in treatment response. Clinical trial registration: ClinicalTrials.gov (NCT05103319).

What is this study about? This study examined data of patients with chronic pain who received an infusion at our hospital with two drugs, lidocaine and ketamine, in an effort to reduce pain. We examined the records of 319 patients and a total of 2995 infusion protocols to gather our data. We wanted to know how much and for how long pain was reduced by these infusions. Additionally, we tried to identify the specific features of patients who profited the most during our infusions. We also had a look at the side effects of the infusions and wanted to know if patients could reduce their daily pain medication intake when receiving infusions. What were the results? On average, people had less pain for 10 days after the infusions. Women seemed to benefit more than men. Otherwise, we were unable to identify specific features that predicted how much a patient would benefit. Side effects occurred only during the infusions and for a short period afterward. In addition, 41.4% of patients who took pain medication daily were able to reduce their intake. What do the results mean? These results support our clinical experience that infusions with lidocaine and ketamine are safe and can contribute to reduced pain in patients with chronic pain, at least in the short term, and for some patients even longer.

[Anaesthesia and pain therapy: perioperative management of patients with complex regional pain syndrome]. / Patienten mit einem komplexen regionalen Schmerzsyndrom (CRPS) - Perioperatives Management und schmerztherapeutische Therapieformen.

The complex regional pain syndrome (CRPS) is indeed a very complex pain situation. The treatment of CRPS is challenging. Patients with an acute CRPS or a CRPS in the past, who have to undergo surgery, provide a special situation. Recommendations for the management of such patients will be described in the article. High degree of evidence exists for high doses of vitamin C to prevent the development of a CRPS in trauma patients.

Analgesic benefit of metamizole and ibuprofen vs. either medication alone: a randomized clinical trial.

BACKGROUND: Postoperative pain relief remains a key problem after surgery. Multimodal pain therapy has proven beneficial in alleviating pain to a certain extent. However, when combining non-opioids, the focus has been on NSAIDs and paracetamol, but effects of combined use are only moderate. Metamizole could be a potent adjunct, due to its preclusion in several countries, data on its combined use are sparse, despite its common use in many countries. The aim of this study was to examine whether the combination of metamizole and ibuprofen is superior in relieving postoperative pain to either drug alone. METHODS: For this randomized, placebo-controlled, cross-over study, 35 patients undergoing bilateral lower third molar extraction were randomized. Each patient received three applications of 1000 mg metamizole + 400 mg ibuprofen for surgery on one side and either 1000 mg metamizole + placebo or 400 mg ibuprofen + placebo on the other side. Pain ratings, rescue-medication (tramadol), and sleep were assessed for 18 hours. RESULTS: The combined treatment of metamizole and ibuprofen showed lower mean pain scores over 12 hours than ibuprofen (2.4±1.3 vs 3.8±1.6; P=0.005). Further, combined treatment showed lower mean pain scores over 6 hours than ibuprofen (2.0±1.2 vs. 3.1±1.6; P=0.022) or metamizole alone (2.0±1.2 vs. 3.3±1.7; P=0.015). Consumption of rescue medication was lowest in the combination-group (25% vs. 46%-metamizole; 50%-ibuprofen). The trial was stopped prematurely as the COVID-pandemic halted elective surgeries. CONCLUSIONS: Combined use enables superior pain control compared to ibuprofen after molar extraction and tends to be superior to metamizole alone. The premature study-termination may overestimate this effect.

Pain response to cannabidiol in opioid-induced hyperalgesia, acute nociceptive pain, and allodynia using a model mimicking acute pain in healthy adults in a randomized trial (CANAB II).

ABSTRACT: Opioids in general and remifentanil in particular can induce hyperalgesia. Preclinical data suggest that cannabidiol might have the capacity to reduce opioid-induced hyperalgesia (OIH). Thus, we investigated the effect of oral cannabidiol on OIH in healthy volunteers using an established pain model. Twenty-four healthy participants were included in this randomized, double-blinded, crossover study and received either a 1600-mg single-dose oral cannabidiol or placebo. Hyperalgesia, allodynia, and pain were induced by intracutaneous electrical stimulation. To provoke OIH, participants recieved an infusion of 0.1 µg/kg/min remifentanil over a time frame of 30 minutes, starting 100 minutes after oral cannabidiol ingestion. The primary outcome was the area of hyperalgesia (in square centimetres) up to 60 minutes after remifentanil administration. The area of allodynia (in square centimetres) and pain (numeric rating scale) were also assessed.Cannabidiol had no significant effect on hyperalgesia, allodynia, or pain at any time point of measurement compared with placebo. The area of hyperalgesia after remifentanil administration significantly increased compared with baseline (17.0 cm 2 [8.1-28.7] vs 25.3 cm 2 [15.1-39.6]; P = 0.013). Mean cannabidiol blood levels were 4.1 ± 3.0 µg/L (mean ± SD) at 130 minutes after ingestion and were 8.2 µg/L ± 6.9 µg/L (mean ± SD) at 200 minutes. Cannabidiol was well tolerated. We conclude that a high single-oral dose of 1600-mg cannabidiol is not effective in reducing OIH. Before excluding an effect of cannabidiol on OIH, research should focus on drug formulations enabling higher cannabidiol concentrations.

Pain response to cannabidiol in induced acute nociceptive pain, allodynia, and hyperalgesia by using a model mimicking acute pain in healthy adults in a randomized trial (CANAB I).

ABSTRACT: Preclinical studies have demonstrated the analgesic potential of cannabidiol (CBD). Those suggesting an effect on pain-processing receptors have brought CBD back into focus. This study assessed the effect of CBD on acute pain, hyperalgesia, and allodynia compared with placebo. Twenty healthy volunteers were included in this randomized, placebo-controlled, double-blinded, crossover study assessing pain intensities (using numeric rating scale), secondary hyperalgesia (von Frey filament), and allodynia (dry cotton swab) in a well-established acute pain model with intradermal electrical stimulation. The authors compared the effect of 800-mg orally administered CBD on pain compared with placebo. They further examined the effect on hyperalgesia and allodynia. Cannabidiol whole blood levels were also measured. Pain ratings (mean ± SD) did not differ significantly after CBD application compared with placebo (5.2 ± 0.7 vs 5.3 ± 0.7, P-value 0.928), neither did the areas of hyperalgesia and allodynia differ significantly after CBD application compared with placebo (hyperalgesia 23.9 ± 19.2 cm2 vs 27.4 ± 17.0 cm2, P-value 0.597; allodynia 16.6 ± 13.1 cm2 vs 17.3 ± 14.1 cm2, P-value 0.884). The CBD whole blood level (median, first to third quartile) was 2.0 µg/L (1.5-5.1) 60 minutes and 5.0 µg/L (4.0-10.4) 130 minutes after CBD application. Although the oral application of 800-mg CBD failed to show a significant effect, it is important to focus future research on different dosing, routes of administration, and CBD as a part of multimodal treatment strategies before negating its effects on acute pain.