Analgesic Clinical Trials Research Articles

Lateness of Acetaminophen and Non-steroidal Anti-inflammatory Drug Administrations in a Retrospective Cohort of Medication Administration Records Among Patients After Cesarean Delivery.

In an earlier study of patients after cesarean delivery, the concurrent versus alternating administration of acetaminophen and non-steroidal anti-inflammatory drugs was associated with a substantial reduction in total postoperative opioid use. This likely pharmacodynamic effect may differ if the times when nurses administer acetaminophen and non-steroidal anti-inflammatory drugs often differ substantively from when they are due. Weexamined the "lateness" of analgesic dose administration times, the positive difference ifadministered late, and the negative value ifearly. The retrospective cohort study used all 67,900 medication administration records for scheduled (i.e., not "as needed") acetaminophen, ibuprofen, and ketorolac among all 3,163 cesarean delivery cases at the University of Iowa between January 2021 and December 2023. Barcode scanning at the patient's bedside was used right before each medication administration. There were 95% of doses administered over a 4.8-hour window, from 108 minutes early (97.5% one-sided upper confidence limit 105 minutes early) to 181 minutes late (97.5% one-sided lower limit 179 minutes late). Fewer than half of doses (46%, P <0.0001) were administered ±30minutes of the due time. The intraclass correlation coefficient was approximately 0.11, showing that there were small systematic differences among patients. There likewise were small to no systematic differences in lateness based on concurrent administrations ofacetaminophen and ibuprofen or ketorolac, time of the day that medications were due, weekday, year, or number of medications to be administered among all such patients within 15 minutes. Other hospitals should check the lateness of medication administration when that would change their ability to perform or apply the results of analgesic clinical trials (e.g., simultaneous versus alternating administration).

The price of pain relief, or should non-invasive medical devices be treated differently in analgesic clinical trials?

This journal recently published a paper entitled "A virtual reality system for pain and anxiety management during outpatient hysteroscopy - A randomized-control trial." (Fouks et al., 202*). In this study involving 82 patients, the authors failed to evidence any superiority of immersive virtual reality (VR) vs. care-as-usual (CAU), while other published studies, such as several ones in paediatrics (Eijlers et al. 2019; Lambert et al. 2020), were in favour of VR. Either so-called "negative" or "positive", any new trial is important to increase our knowledge about this emergent therapy.

Quantifying noxious-evoked baseline sensitivity in neonates to optimise analgesic trials.

Despite the high burden of pain experienced by hospitalised neonates, there are few analgesics with proven efficacy. Testing analgesics in neonates is experimentally and ethically challenging and minimising the number of neonates required to demonstrate efficacy is essential. EEG (electroencephalography)-derived measures of noxious-evoked brain activity can be used to assess analgesic efficacy; however, as variability exists in neonate's responses to painful procedures, large sample sizes are often required. Here, we present an experimental paradigm to account for individual differences in noxious-evoked baseline sensitivity which can be used to improve the design of analgesic trials in neonates. The paradigm is developed and tested across four observational studies using clinical, experimental, and simulated data (92 neonates). We provide evidence of the efficacy of gentle brushing and paracetamol, substantiating the need for randomised controlled trials of these interventions. This work provides an important step towards safe, cost-effective clinical trials of analgesics in neonates.

General risks of harm with cannabinoids, cannabis, and cannabis-based medicine possibly relevant to patients receiving these for pain management: an overview of systematic reviews.

The growing demand for improved pain treatments together with expanding legalization of, and access to, cannabinoids, cannabis, and cannabis-based medicines has intensified the focus on risk-benefit considerations in pain management. Given limited harms data from analgesic clinical trials, we conducted an overview of systematic reviews focused on all harms possibly relevant to patients receiving cannabinoids for pain management. This PROSPERO-registered, PRISMA-compliant systematic overview identified 79 reviews, encompassing over 2200 individual reports about psychiatric and psychosocial harms, cognitive/behavioral effects, motor vehicle accidents, cardiovascular, respiratory, cancer-related, maternal/fetal, and general harms. Reviews, and their included studies, were of variable quality. Available evidence suggests variable associations between cannabis exposure (ranging from monthly to daily use based largely on self-report) and psychosis, motor vehicle accidents, respiratory problems, and other harms. Most evidence comes from settings other than that of pain management (eg, nonmedicinal and experimental) but does signal a need for caution and more robust harms evaluation in future studies. Given partial overlap between patients receiving cannabinoids for pain management and individuals using cannabinoids for other reasons, lessons from the crisis of oversupply and overuse of opioids in some parts of the world emphasize the need to broadly consider harms evidence from real-world settings. The advancement of research on cannabinoid harms will serve to guide optimal approaches to the use of cannabinoids for pain management. In the meantime, this evidence should be carefully examined when making risk-benefit considerations about the use of cannabinoids, cannabis, and cannabis-based medicine for chronic pain.

Factors with impact on magnitude of the placebo response in randomized, controlled, cross-over trials in peripheral neuropathic pain.

The presence and magnitude of placebo responses is important for the outcome in clinical trials of analgesics. This explorative study aimed at identifying patients and trial-specific factors with impact on this response in randomized, controlled, cross-over trials in peripheral neuropathic pain. Data were derived from 7 trials and included observations on pinprick hyperalgesia, allodynia, and pain on repetitive stimulation. The studies were all performed by the same collaboration group in Denmark. Pain was rated daily using numeric 0 to 10 point rating scales (NRS) and placebo response was calculated as the difference in weekly average or median numeric rating scale from baseline to the last week of treatment. A clinically meaningful placebo response was defined as more than 30% reduction of pain on placebo. In 318 individual observations, the response was on average small (0.17 points, range -4.5 to 6). There was no significant impact on size of placebo response of trial-specific factors such as treatment sequence and chance of having placebo treatment in each period or of the patient-specific factors age, sensory signs, and pain symptoms. The findings were similar in patients having placebo in the first treatment period. There was no marked difference between patients with (n = 43) and without (n = 275) a clinically meaningful placebo response with respect to the patient-specific factors including frequency of sensory signs and symptoms. In conclusion, this study on cross-over trials in peripheral neuropathic pain found no robust impact of trial and patient-specific factors on the placebo response.

Oral morphine analgesia for preventing pain during invasive procedures in non-ventilated premature infants in hospital: the Poppi RCT

Background Identifying better pain management strategies for painful procedures performed in neonatal care is a clinical priority. Retinopathy of prematurity screening and heel-lance blood tests are essential clinical procedures, but adequate pain relief is not currently provided because of a lack of evidence-based analgesia. Morphine provides effective analgesia in older children and adults, but efficacy in infants is controversial. Morphine is, however, commonly used intravenously for sedation in ventilated infants. Objective The primary objective was to investigate whether or not a single 100 µg/kg morphine sulphate dose administered orally prior to painful clinical procedures provides effective analgesia. Design Single-centre, prospective, randomised controlled trial. Setting John Radcliffe Hospital, Oxford, UK. Participants Thirty-one infants of 34–42 weeks’ gestational age, requiring a heel lance and retinopathy of prematurity screening on the same test occasion. Interventions The study interventions were 100 µg/kg of oral morphine sulphate (intervention arm) or placebo (control arm) 1 hour before the clinically required procedures. Main outcome measures There were two co-primary outcomes: Premature Infant Pain Profile-Revised score (a higher score implies more nociceptive processing) during the 30-second period after retinopathy of prematurity screening, and the magnitude of noxious-evoked brain activity (a higher activity implies more nociceptive processing) following the heel lance. Physiological stability and safety were secondary outcomes. Results After 31 participants were randomised (30 studied and one withdrew), the predefined safety stopping boundary was passed as 3 of the 15 infants who received morphine had apnoeas requiring resuscitation with non-invasive positive-pressure ventilation in the 24 hours after drug administration, compared with 0 of the 15 infants who received placebo [difference in proportion 0.2, 80% confidence interval (adjusted to allow for planned multiple analyses) 0.05 to 1.00; p = 0.085]. The trial was therefore stopped because of profound respiratory adverse effects of morphine without suggestion of analgesic efficacy. There was no significant difference between the trial arms for either primary outcome (Premature Infant Profile-Revised score following retinopathy of prematurity screening mean score ± standard deviation – morphine: 11.1 ± 3.2; Premature Infant Pain Profile-Revised score following retinopathy of prematurity screening mean score ± standard deviation – placebo: 10.5 ± 3.4; mean difference in Premature Infant Pain Profile-Revised score following retinopathy of prematurity screening score 0.5, 95% confidence interval –2.0 to 3.0, p = 0.66; noxious-evoked brain activity following heel lancing median activity – morphine: 0.99, interquartile range 0.40–1.56; noxious-evoked brain activity following heel lancing median activity – placebo: 0.75, interquartile range 0.33–1.22; and median difference in noxious-evoked brain activity following heel lancing 0.25, 95% confidence interval –0.16 to 0.80, p = 0.25). Limitations The trial lacked power for the primary outcome measures because of early cessation. However, there was a trend across modalities favouring placebo, suggesting that it was unlikely that a clinically significant analgesic benefit would have been detected in the original proposed sample of 156 infants. Conclusions The administration of 100 µg/kg of oral morphine to non-ventilated premature infants has the potential for harm without analgesic benefit. Oral morphine is not recommended for retinopathy of prematurity screening, and caution is strongly advised if this is being considering for other acute painful procedures in non-ventilated premature infants. Future work Further clinical trials are essential to ascertain effective pain management for retinopathy of prematurity screening. Using multimodal measures with detailed physiological recordings provides a rigorous approach to assess analgesic efficacy and adverse effects, leading to greater mechanistic understanding of the drug effects. This is essential in future clinical trials of analgesics in infants. Patient and public involvement The research team worked closely with an on-site charity during the trial design, conduct, oversight and dissemination. Trial registration Clinical Controlled Trials ISRCTN82342359; EudraCT 2014-003237-25. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership. Funding was also received for the trial from the Wellcome Trust (reference numbers 095802 and 102076). The report will be published in full in Efficacy and Mechanism; Vol. 6, No. 9. See the National Institute for Health Research’s Journals Library website for further project information.

The relationship between the reporting of euphoria events and early treatment responses to pregabalin: an exploratory post-hoc analysis.

BackgroundEuphoria is a complex, multifactorial problem that is reported as an adverse event in clinical trials of analgesics including pregabalin. The relationship between the reporting of euphoria events and pregabalin early treatment responses was examined in this exploratory post-hoc analysis.MethodsData were from patients with neuropathic or non-neuropathic chronic pain enrolled in 40 randomized clinical trials, who received pregabalin (75–600 mg/day) or placebo. Reports of treatment-emergent euphoria events were based on the Medical Dictionary of Regulatory Activities preferred term “euphoric mood”. Prevalence rates of euphoria events overall and by indication were assessed. Post-treatment endpoints included ≥30% improvements in pain and sleep scores up to 3 weeks as well as a ≥1-point improvement in daily pain score up to 11 days after treatment.Results13,252 patients were analyzed; 8,501 (64.1%) and 4,751 (35.9%) received pregabalin and placebo, respectively. Overall, 1.7% (n=222) of patients reported euphoria events. Among pregabalin-treated patients, a larger proportion who reported euphoria events achieved an early pain response compared with those who did not report euphoria (30% pain responders in week 1 with euphoria events [43.0%], without euphoria events [24.2%]). Results were similar for weeks 2 and 3. For Days 2–11, a larger proportion of pregabalin-treated patients with (relative to without) euphoria events were 1-point pain responders. Findings were similar in pregabalin-treated patients for sleep endpoints (30% sleep responders in week 1 with euphoria events [50.7%], without euphoria events [36.1%]). Similar results were found for weeks 2 and 3. Patients who received placebo showed similar patterns, although the overall number of them who reported euphoria events was small (n=13).ConclusionIn patients who received pregabalin for neuropathic or non-neuropathic chronic pain, those who experienced euphoria events may have better early treatment responses than those who did not report euphoria events.

The ACTTION Guide to Clinical Trials of Pain Treatments: standing on the shoulders of giants.

The ACTTION Guide to Clinical Trials of Pain Treatments: standing on the shoulders of giants.

Designing and conducting proof-of-concept chronic pain analgesic clinical trials.

Introduction:The evolution of pain treatment is dependent on successful development and testing of interventions. Proof-of-concept (POC) studies bridge the gap between identification of a novel target and evaluation of the candidate intervention's efficacy within a pain model or the intended clinical pain population.Methods:This narrative review describes and evaluates clinical trial phases, specific POC pain trials, and approaches to patient profiling.Results:We describe common POC trial designs and their value and challenges, a mechanism-based approach, and statistical issues for consideration.Conclusion:Proof-of-concept trials provide initial evidence for target use in a specific population, the most appropriate dosing strategy, and duration of treatment. A significant goal in designing an informative and efficient POC study is to ensure that the study is safe and sufficiently sensitive to detect a preliminary efficacy signal (ie, a potentially valuable therapy). Proof-of-concept studies help avoid resources wasted on targets/molecules that are not likely to succeed. As such, the design of a successful POC trial requires careful consideration of the research objective, patient population, the particular intervention, and outcome(s) of interest. These trials provide the basis for future, larger-scale studies confirming efficacy, tolerability, side effects, and other associated risks.

Current methods and challenges for acute pain clinical trials.

The clinical setting of acute pain has provided some of the first approaches for the development of analgesic clinical trial methods. This article reviews current methods and challenges and provides recommendations for future design and conduct of clinical trials of interventions to treat acute pain. Growing knowledge about important diverse patient factors as well as varying pain responses to different acute pain conditions and surgical procedures has highlighted several emerging needs for acute pain trials. These include development of early-phase trial designs that minimize variability and thereby enhance assay sensitivity, minimization of bias through blinding and randomization to treatment allocation, and measurement of clinically relevant outcomes such as movement-evoked pain. However, further improvements are needed, in particular for the development of trial methods that focus on treating complex patients at high risk of severe acute pain.

Why We should Assess Patients' Expectations in Clinical Trials.

Most of the analgesic clinical trials have failed to succeed over the past years because of the occurrence of large placebo responses. Patients’ expectations about the therapeutic benefit represent a major determinant of the placebo response. Therefore, assessing patients’ expectations should become the rule in any clinical trial. This would allow us to better interpret therapeutic outcomes when comparing placebo and verum groups.

Caregiver placebo effect in analgesic clinical trials for cats with naturally occurring degenerative joint disease-associated pain

A literature review identified six placebo-controlled studies of analgesics in client-owned cats with degenerative joint disease-associated pain. Five studies with 96 cats had available data. Caregiver responses on a clinical...

Development and preliminary validation of the focused analgesia selection test to identify accurate pain reporters.

Clinical trials of analgesics have been plagued with poor assay sensitivity due, in part, to variability in subjects’ pain reporting. Herein, we develop and evaluate the focused analgesia selection test (FAST), a method to measure patients’ pain reporting skills. Subjects with osteoarthritis of the hip, knee, and/or ankle with pain intensity of ≥3/10 on a 0–10 numerical rating scale were enrolled. Subjects underwent the FAST procedure, which consists of recording subjects’ pain reports in response to repeated administration of thermal noxious stimuli of various intensities applied on the arm with the Medoc® Thermal Sensory Analyzer II. Subjects also rated non-noxious stimuli consisting of visual contrast rating. After performing an exercise task, subjects also rated clinical pain and were asked to report whether their pain had increased, decreased, or stayed the same. Overall, 88 subjects were enrolled, and 83 were included in the analyses. FAST’s outcomes including the R2, intraclass correlation coefficient (ICC), and coefficient of variation (CoV) indicated that subjects’ pain reporting skills were widely distributed. Higher FAST ICC significantly predicted greater changes in clinical pain following exercise (p=0.017), whereas the visual contrast test did not predict postexercise pain. FAST is the first method that measures subjects’ pain reporting skills. Using FAST to enrich clinical trials with “good” pain reporters (with high FAST ICC) could increase assay sensitivity. Further evaluation of FAST is ongoing.

Mechanisms for Research Support.

During the second day of the Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) symposium 2016, 3 invited speakers focused on future directions for the PANDA group. This session, entitled "The Way Forward," included 3 talks on how other groups have organized through public-private partnerships (ACTTION), obtained NIH funding, and how to better communicate a research message. Dr Robert H. Dworkin spoke on the mission of the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities and Networks (ACTTION), which is a public-private partnership with the United States Food and Drug Administration that pushes forward research related to pain and analgesics. Dr Tracy King discussed National Institute of Health funding for future studies in neurocognitive development after exposure to anesthetics. Dr Sharon Hertz discussed how the PANDA group might better craft their message to the public regarding effects of analgesics on neurocognitive development. Through their talks, the above speakers provided a clear route for the way forward in regard to research, funding, and messaging for the PANDA group.

Participant Preferences for Pharmacologic Chronic Pain Treatment Trial Characteristics: An ACTTION Adaptive Choice-Based Conjoint Study.

This article presents the preferences of individuals with chronic pain conditions regarding modifiable pain treatment trial characteristics (eg, number of study visits, payment, treatment allocation). These findings may help to improve enrollment into analgesic clinical trials and in turn accelerate the development of new pain treatments.

Adverse Event Reporting in Clinical Trials of Intravenous and Invasive Pain Treatments: An ACTTION Systematic Review.

This systematic review of AE reporting in intravenous and invasive pain treatment trials shows that little improvement has been made since the 2004 CONSORT harms reporting guidelines. Better assessment and reporting of treatment AEs is necessary to understand the full clinical effect of intravenous and invasive treatments.

Preoperative analgesics for additional pain relief in children and adolescents having dental treatment.

Fear of dental pain is a major barrier to treatment for children who need dental care. The use of preoperative analgesics has the potential to reduce postoperative discomfort and intraoperative pain. We reviewed the available evidence to determine whether further research is warranted and to inform the development of prescribing guidelines. This is an update of a Cochrane review published in 2012. To assess the effects of preoperative analgesics for intraoperative or postoperative pain relief (or both) in children and adolescents undergoing dental treatment without general anaesthesia or sedation. We searched the following electronic databases: Cochrane Oral Health's Trials Register (to 5 January 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2015, Issue 12), MEDLINE via OVID (1946 to 5 January 2016), EMBASE via OVID (1980 to 5 January 2016), LILACS via BIREME (1982 to 5 January 2016) and the ISI Web of Science (1945 to 5 January 2016). We searched ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform for ongoing trials to 5 January 2016. There were no restrictions regarding language or date of publication in the searches of the electronic databases. We handsearched several specialist journals dating from 2000 to 2011.We checked the reference lists of all eligible trials for additional studies. We contacted specialists in the field for any unpublished data. Randomised controlled clinical trials of analgesics given before dental treatment versus placebo or no analgesics in children and adolescents up to 17 years of age. We excluded children and adolescents having dental treatment under sedation (including nitrous oxide/oxygen) or general anaesthesia. Two review authors assessed titles and abstracts of the articles obtained from the searches for eligibility, undertook data extraction and assessed the risk of bias in the included studies. We assessed the quality of the evidence using GRADE criteria. We included five trials in the review, with 190 participants in total. We did not identify any new studies for inclusion from the updated search in January 2016.Three trials were related to dental treatment, i.e. restorative and extraction treatments; two trials related to orthodontic treatment. We did not judge any of the included trials to be at low risk of bias.Three of the included trials compared paracetamol with placebo, only two of which provided data for analysis (presence or absence of parent-reported postoperative pain behaviour). Meta-analysis of the two trials gave arisk ratio (RR) for postoperative pain of 0.81 (95% confidence interval (CI) 0.53 to 1.22; two trials, 100 participants; P = 0.31), which showed no evidence of a benefit in taking paracetamol preoperatively (52% reporting pain in the placebo group versus 42% in the paracetamol group). One of these trials was at unclear risk of bias, and the other was at high risk. The quality of the evidence is low. One study did not have any adverse events; the other two trials did not mention adverse events.Four of the included trials compared ibuprofen with placebo. Three of these trials provided useable data. One trial reported no statistical difference in postoperative pain experienced by the ibuprofen group and the control group for children undergoing dental treatment. We pooled the data from the other two trials, which included participants who were having orthodontic separator replacement without a general anaesthetic, to determine the effect of preoperative ibuprofen on the severity of postoperative pain. There was a statistically significant mean difference in severity of postoperative pain of -13.44 (95% CI -23.01 to -3.88; two trials, 85 participants; P = 0.006) on a visual analogue scale (0 to 100), which indicated a probable benefit for preoperative ibuprofen before this orthodontic procedure. However, both trials were at high risk of bias. The quality of the evidence is low. Only one of the trials reported adverse events (one participant from the ibuprofen group and one from the placebo group reporting a lip or cheek biting injury). From the available evidence, we cannot determine whether or not preoperative analgesics are of benefit in paediatric dentistry for procedures under local anaesthetic. There is probably a benefit in using preoperative analgesics prior to orthodontic separator placement. The quality of the evidence is low. Further randomised clinical trials should be completed with appropriate sample sizes and well defined outcome measures.

Maintenance of Blinding in Clinical Trials and the Implications for Studying Analgesia Using Cannabinoids.

The design of analgesic clinical trials invariably involves a comparison between placebo and active study medication. An assumption is made that treatment effects can be approximated by subtracting the response to placebo from that attained with the use of active study medication. However, the psychoactivity of cannabinoids may unmask their presence and lead to an expectation and/or conditioning of pain relief. For example, study participants biased toward the belief that cannabis is beneficial for their condition might be more inclined to report positive effects if they were to accurately identify the active treatment because of its psychoactivity. This may lead to incorrect assumptions regarding the efficacy of a cannabinoid. Methodologies designed to counteract unmasking need to be implemented in the design phase of a study. During the clinical trial, it is also important to query participants as to which treatment they believe they have received. Blinding can be considered to be preserved when the accuracy of treatment guesses is not considerably different than random guessing, which is estimated to be correct 50% of the time. After a study has been completed, the use of statistical methodologies such as regression and mediation analysis are worthy of consideration to see whether psychoactive effects biased the results.

(171) Characterization and prediction of placebo responders in peripheral neuropathic patients in a 4-week analgesic clinical trial

(171) Characterization and prediction of placebo responders in peripheral neuropathic patients in a 4-week analgesic clinical trial

Research design considerations for single-dose analgesic clinical trials in acute pain: IMMPACT recommendations.

This article summarizes the results of a meeting convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) on key considerations and best practices governing the design of acute pain clinical trials. We discuss the role of early phase clinical trials, including pharmacokinetic-pharmacodynamic (PK-PD) trials, and the value of including both placebo and active standards of comparison in acute pain trials. This article focuses on single-dose and short-duration trials with emphasis on the perioperative and study design factors that influence assay sensitivity. Recommendations are presented on assessment measures, study designs, and operational factors. Although most of the methodological advances have come from studies of postoperative pain after dental impaction, bunionectomy, and other surgeries, the design considerations discussed are applicable to many other acute pain studies conducted in different settings.