The Importance of the Treatment Rationale for Pain in Animal-Assisted Interventions: A Randomized Controlled Trial in Healthy Participants.

Animal-assisted interventions (AAIs) is a promising treatment approach for pain, but possible mechanisms still need to be elucidated. This study set out to investigate the analgesic effects of an animal provided with a treatment rationale in a randomized controlled trial employing a standardized experimental heat-pain paradigm. We randomly assigned 128 healthy participants to: dog treatment (DT), placebo treatment (PT), dog and placebo treatment (DPT), and no treatment (NT). Primary outcomes were heat-pain tolerance and the corresponding self-reported ratings of pain unpleasantness and intensity. Results revealed no differences in heat-pain tolerance between the conditions. However, participants in the DT condition experienced heat-pain as significantly less unpleasant at the limit of their tolerance compared to participants in the NT condition (estimate = -0.96, CI = -1.58 to 0.34, P = .010). Participants in the DT condition also showed lower ratings of pain intensity at the limit of their tolerance compared to participants in the NT condition (estimate = -0.44, CI = -0.89 to 0.02, P = .060). This study indicates that a dog has analgesic effects on pain perception when integrated into the treatment rationale. We assume that providing a treatment rationale regarding the animal is important in AAIs for pain. PERSPECTIVE: This study shows that the presence of an animal is not sufficient for animal-assisted interventions (AAIs) to have an analgesic effect on pain unless they are provided with a treatment rationale. This could imply that not only the animal but also contextual factors are important in AAIs. TRIAL REGISTRATION: Clinical Trials NCT04361968.

Could we use the comfort score instead of the numeric rating pain score? A proof of concept pilot study.

INTRODUCTION: Asking patients about pain in the Emergency Department (ED) when deriving a pain score may aggravate perception of pain due to the nocebo-effect. A strategy for diminishing this nocebo-effect is cognitive reframing. Cognitive reframing of the frequently used pain score (PS) in the ED could theoretically be obtained by using the comfort score (CS). The aim of this study was to evaluate whether or not the CS and PS are interchangeable and therefore, whether or not the CS could safely be used in ED patients. METHODS: In this prospective pilot study we enrolled patients with pain visiting the ED. Participants were asked for both PS and CS in randomized order. CS were inverted (ICS) and compared with PS using the using the Wilcoxon signed rank test. Secondarily we evaluated for patient score preference. RESULTS: In total 100 patients were enrolled. The median PS in these participants was 6 (IQR 4-7) and median ICS was 5 (IQR 3-6). In total, 15 (15%) of the PS and ICS were identical Medians did not differ significantly (p = .115). In 33% of the participants the total difference between the PS and ICS was >2. Participants preferred to be asked for PS over CS (43 vs 15%, p < .00). CONCLUSION: This proof of concept study suggest interchangeability of the PS and the ICS in patients with pain in the ED. However, while not statistically significant, 33% of the patients had a possible clinical significant difference in score outcome, potentially over- or underestimating the patients pain. Whether or not this can be used as a tool for cognitive reframing to reduce perception of pain and medication consumption has yet to be studied.

Study protocol for a randomised controlled trial of diacerein versus placebo to treat knee osteoarthritis with effusion-synovitis (DICKENS).

BACKGROUND: There is an unmet need for treatments for knee osteoarthritis (OA). Effusion-synovitis is a common inflammatory phenotype of knee OA and predicts knee pain and structural degradation. Anti-inflammatory therapies, such as diacerein, may be effective for this phenotype. While diacerein is recommended for alleviating pain in OA patients, evidence for its effectiveness is inconsistent, possibly because studies have not targeted patients with an inflammatory phenotype. Therefore, we will conduct a multi-centre, randomised, placebo-controlled double-blind trial to determine the effect of diacerein on changes in knee pain and effusion-synovitis over 24 weeks in patients with knee OA and magnetic resonance imaging (MRI)-defined effusion-synovitis. METHODS: We will recruit 260 patients with clinical knee OA, significant knee pain, and MRI-detected effusion-synovitis in Hobart, Melbourne, Adelaide, and Perth, Australia. They will be randomly allocated to receive either diacerein (50mg twice daily) or identical placebo for 24 weeks. MRI of the study knee will be performed at screening and after 24 weeks of intervention. The primary outcome is improvement in knee pain at 24 weeks as assessed by a 100-mm visual analogue scale (VAS). Secondary outcomes include improvement in volumetric (ml) and semi-quantitative (Whole-Organ Magnetic Resonance Imaging Score, 0-3) measurements of effusion-synovitis using MRI over 24 weeks, and improvement in knee pain (VAS) at 4, 8, 12, 16, and 20 weeks. Intention-to-treat analyses of primary and secondary outcomes will be performed as the primary analyses. Per protocol analyses will be performed as the secondary analyses. DISCUSSION: This study will provide high-quality evidence to determine whether diacerein improves pain, changes disease trajectory, and slows disease progression in OA patients with effusion-synovitis. If diacerein proves effective, this has the potential to significantly benefit the substantial proportion (up to 60%) of knee OA patients with an inflammatory phenotype. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry ACTRN12618001656224 . Registered on 08 October 2018.

Definitive urine drug test findings in patients prescribed opioids for pain from a large national database.

OBJECTIVE: Clinicians and policymakers have been wrestling with the appropriateness and safety of opioid therapy during the opioid crisis. Policy and clinical decisions have often been made without much current data on trends in drug use in patients with pain. Thus, we evaluated definitive urine drug test (UDT) results in patients being treated for pain to see if those taking their prescribed opioids were less likely to be positive for the primary illicit drugs currently driving overdose deaths: cocaine, heroin, fentanyl, and methamphetamine. DESIGN, SETTING, AND PATIENTS: A cross-sectional study of UDT results from January 1, 2015 to September 30, 2021, from 600,000 patient specimens submitted for testing by pain management specialists. INTERVENTIONS: UDT by liquid chromatography-tandem mass spectrometry as ordered by the treating clinician. MAIN OUTCOME MEASURES: Presence of other substances stratified by whether a patient's prescribed opioid was found. RESULTS: The presence of cocaine, heroin, fentanyl, and methamphetamine for the total population was low (<5 percent). Of the 347,092 patients prescribed opioids, 76 percent (n = 264,961) were positive on UDT for their prescribed opioid ("consistent"). Compared to patients without their prescribed opioid present ("inconsistent"), patients consistent with therapy were 54 percent (incidence rate ratio (IRR) 1.54, 95 percent confidence interval (CI) 1.47-1.59) less likely to be positive for cocaine, 47 percent [IRR 1.47, 95 percent CI 1.34-1.57] less likely to be positive for heroin, and 35 percent [IRR 1.35, 95 percent CI 1.24-1.45] less likely to be positive for methamphetamine, p < 0.001. Differences between the groups for fentanyl were not significant. CONCLUSIONS: Overall positivity rates for cocaine, heroin, fentanyl, and methamphetamine were low. Patients with prescribed opioid present were less likely to be positive for cocaine, heroin, or methamphetamine. Patterns of substance use within this pain management population should be used to inform ongoing policy decisions.

Common Selfcare Indications of Pain Medications in Children.

Pain has a multifaceted impact on individuals worldwide, affecting their physical functioning, emotional well-being, and quality of life. Children (age < 18 years) have a high prevalence of conditions associated with pain, such as toothache, headache, earache, sore throat, and respiratory tract infections, many of which may be accompanied by fever. Globally, the pharmacologic treatment of pain in pediatric patients is limited largely to nonopioid analgesics, and dosing must account for differences in age, weight, metabolism, and risk of adverse effects. This narrative review summarizes the findings of a literature search on the pediatric indications, dosing approaches, dosing guidelines, and pharmacokinetics of paracetamol and ibuprofen, which are common pain medications available globally for self-care use in children. The review also discusses the risks and benefits associated with these agents. The current roles of paracetamol and ibuprofen in the symptomatic management of coronavirus disease 2019 (COVID-19) infection and in the management of post-COVID-19 immunization symptoms in children are also discussed. Therefore, while a very large amount of data over several decades is available for paracetamol and ibuprofen, an urgent need exists for well-designed studies of these medications for the management of pain and fever in pediatric patients with COVID-19 to ensure optimal relief with minimal toxicity.

Society of Pain and Palliative Care Pharmacists White Paper on the Role of Opioid Stewardship Pharmacists.

Opioid stewardship is one essential function of pain and palliative care pharmacists and a critical need in the United States. In recent years, this country has been plagued by two public health emergencies: an opioid crisis and the COVID-19 pandemic, which has exacerbated the opioid epidemic through its economic and psychosocial toll. To develop an opioid stewardship program, a systematic approach is needed. This will be detailed in part here by the Opioid Stewardship Taskforce of the Society of Pain and Palliative Care Pharmacists (SPPCP), focusing on the role of the pharmacist. Many pain and palliative care pharmacists have made significant contributions to the development and daily operation of such programs while also completing other competing clinical tasks, including direct patient care. To ensure dedicated time and attention to critical opioid stewardship efforts, SPPCP recommends and endorses opioid stewardship models employing a full time, opioid stewardship pharmacist in both the inpatient and outpatient setting. Early research suggests that opioid stewardship pharmacists are pivotal to improving opioid metrics and pain care outcomes. However, further research and development in this area of practice is needed and encouraged.

Follow-Up: Effects of a Pandemic and Isolation on Alcohol and Psychoactive Medication Use in a Population of Rehabilitation and Pain Patients.

OBJECTIVE: The conjunction of the coronavirus disease lockdown and the use of illicit drugs suggests the potential increase in drug usage and opioid deaths. Because of other studies, we felt the need to examine if the lockdown has caused a change in the drug intake of our population of substance abuse and pain management patients. Our initial study indicated no increase in the use of illicit and antianxiety drugs. This study is a continuation of that work. MATERIALS: Urine drug testing is a strategy to reduce harm to patients in pain management and substance abuse treatment programs. We analyzed trends in the clinical drug testing patterns of urine specimens sent by substance abuse and pain clinics to monitor their patients. These specimens were tested by a national clinical laboratory using LC-MS/MS definitive methods. The time frame of these comparative observations was the past six years, including the two years of the pandemic. RESULTS: We observed a 30% reduction in test requests during the second quarter of 2020, the number of test requests and specimens submitted was similar during other times of the six-year period. The observed drug use pattern was similar to the earlier study. Among the patients tested, positivity decreased greatly for the illicit drugs heroin and cocaine but increased for methamphetamine and fentanyl. Use of the antidepressant and anxiolytic drugs remained consistent or declined for some drugs, relative to pre-pandemic patterns. The percent of patients prescribed the opiates morphine and oxycodone decreased, while the use of hydrocodone increased. Positivity for the drug gabapentin increased greatly. The use of alcohol did not increase significantly during the lockdown period. CONCLUSION: In summary, these findings demonstrate relatively consistent drug use, with decreased positivity for high-risk drugs and dangerous drug combinations. We speculate that monitoring of these patients mitigates the possibility of drug misuse and potential overdose and is in concordance with the goals of these monitoring programs.

The effect of the COVID-19 pandemic on opioid prescribing for patients with pleuritic pain.

OBJECTIVE: We sought to understand opioid prescribing for COVID-19 positive and negative patients with pleuritic pain during the first wave of the pandemic. We hypothesized that patients without COVID-19 would be prescribed opioids more frequently intrapandemic compared to prepandemic and postulated that COVID-19 patients would be prescribed opioids more frequently and at greater quantity than their peers. DESIGN: A retrospective observational analysis of electronic health record data. SETTING: A quaternary academic hospital from February through April 2020. PARTICIPANTS: A total of 1,400 of 3,169 adult inpatient hospitalizations involving pleuritic pain were included. MAIN MEASURES: Frequency and average daily dose of opioid prescriptions were analyzed using logistic and linear regression. Opioid prescribing habits were compared pre- and intrapandemic. Hypotheses and primary outcome measures were formulated prior to data collection. KEY RESULTS: During the pandemic, COVID-19 patients were 15.77 absolute percentage points less likely to be prescribed opioids compared to patients without COVID-19 (95 percent confidence interval (CI): -8.98 to -22.56 percent). Patients without COVID-19 were equally likely to be prescribed opioids pre- and intrapandemic (95 percent CI: -9.37 to 2.42 percent). Odds ratio of opioid prescription for COVID-19 patients was 0.44 (95 percent CI: 0.08-0.80). Within those given opioids, COVID-19 patients were prescribed 3.0 percent greater morphine milligram equivalents (MMEs) (95 percent CI: 1.07-5.85 percent). CONCLUSION: During the first wave of the pandemic, COVID-19 patients with pleuritic pain were prescribed opioids less frequently than patients without COVID-19, while patients without COVID-19 were equally likely to be prescribed opioid pre- and intrapandemic. On the other hand, COVID-19 patients treated with opioids were given greater daily MMEs due to the greater utilization of opioid infusions.

Tracheotomy in ventilator-dependent patients with COVID-19: a cross-sectional study of analgesia and sedative requirements.

OBJECTIVE: During March 2020 in the United States, demand for sedatives increased by 91%, that for analgesics rose by 79%, and demand for neuromuscular blockers increased by 105%, all owing to the number of COVID-19 cases requiring invasive mechanical ventilation (MV). We hypothesize that analgesic and sedative requirements decrease following tracheotomy in this patient population. METHODS: In this cross-sectional study, we conducted a retrospective chart review to identify patients with COVID-19 who underwent tracheotomy (T) at an academic medical center between March 2020 and January 2021. We used a paired Student t-test to compare total oral morphine equivalents (OMEs), total lorazepam equivalents, 24-hour average dexmedetomidine dosage in µg/kg/hour, and 24-hour average propofol dosage in µg/kg/minute on days T-1 and T+2 for each patient. RESULTS: Of 50 patients, 46 required opioids before and after tracheotomy (mean decrease of 49.4 mg OMEs). Eight patients required benzodiazepine infusion (mean decrease of 45.1 mg lorazepam equivalents. Fifteen patients required dexmedetomidine infusion (mean decrease 0.34 µg/kg/hour). Seventeen patients required propofol (mean decrease 20.5 µg/kg/minute). CONCLUSIONS: When appropriate personal protective equipment is available, use of tracheotomy in patients with COVID-19 who require MV may help to conserve medication supplies in times of extreme shortages.

Association Between Default Number of Opioid Doses in Electronic Health Record Systems and Opioid Prescribing to Adolescents and Young Adults Undergoing Tonsillectomy.

Importance: In prior studies, decreasing the default number of doses in opioid prescriptions written in electronic health record systems reduced opioid prescribing. However, these studies did not rigorously assess patient-reported outcomes, and few included pediatric patients. Objective: To evaluate the association between decreasing the default number of doses in opioid prescriptions written in electronic health record systems and opioid prescribing and patient-reported outcomes among adolescents and young adults undergoing tonsillectomy. Design, Setting, and Participants: This nonrandomized clinical trial included adolescents and young adults aged 12 to 50 years undergoing tonsillectomy from October 1, 2019, through July 31, 2021, at a tertiary medical center. The treatment group comprised patients from a pediatric otolaryngology service (mostly aged 12-21 years) and the control group comprised patients from a general otolaryngology service (mostly aged 18-25 years). Interventions: Data on patient-reported opioid consumption and outcomes were collected via a survey on postoperative day 14. Based on opioid consumption among pediatric otolaryngology patients before the intervention, the default number of opioid doses was decreased from 30 to 12 in a tonsillectomy order set. This change occurred only for pediatric otolaryngology patients. Main Outcomes and Measures: Proportion of patients with 12 doses in the discharge opioid prescription, number of doses in this prescription, and refills and pain-related visits within 2 weeks of surgery. In a secondary analysis of patients completing the postoperative survey, patient-reported opioid consumption, pain control, sleep disturbance, anxiety, and depression were assessed. Linear or log-linear difference-in-differences models were fitted, adjusting for patients' demographic characteristics and presence of a mental health or substance use disorder. Results: The study included 237 patients (147 female patients [62.0%]; mean [SD] age, 17.3 [3.6] years). Among 131 pediatric otolaryngology patients, 1 of 70 (1.4%) in the preintervention period and 27 of 61 (44.3%) in the postintervention period had 12 doses in the discharge opioid prescription (differential change, 45.5 percentage points; 95% CI, 32.2-58.8 percentage points). Among pediatric otolaryngology patients, the mean (SD) number of doses prescribed in the preintervention period was 22.3 (7.4) and in the postintervention period was 16.1 (6.5) (differential percentage change, -29.2%; 95% CI, -43.2% to -11.7%). The intervention was not associated with changes in refills or pain-related visits. The secondary analysis included 150 patients. The intervention was not associated with changes in patient-reported outcomes except for a 3.5-point (95% CI, 1.5-5.5 points) differential increase in a sleep disturbance score that ranged from 4 to 20, with higher scores indicating poorer sleep quality. Conclusions and Relevance: This nonrandomized clinical trial suggests that evidence-based default dosing settings may decrease perioperative opioid prescribing among adolescents and young adults undergoing tonsillectomy, without compromising analgesia. Trial Registration: ClinicalTrials.gov Identifier: NCT04066829.

Viscosupplementation for knee osteoarthritis: systematic review and meta-analysis.

OBJECTIVE: To evaluate the effectiveness and safety of viscosupplementation for pain and function in patients with knee osteoarthritis. DESIGN: Systematic review and meta-analysis of randomised trials. DATA SOURCES: Searches were conducted of Medline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases from inception to 11 September 2021. Unpublished trials were identified from the grey literature and trial registries. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Randomised trials comparing viscosupplementation with placebo or no intervention for knee osteoarthritis treatment. MAIN OUTCOME MEASURES: The prespecified primary outcome was pain intensity. Secondary outcomes were function and serious adverse events. Pain and function were analysed as standardised mean differences (SMDs). The prespecified minimal clinically important between group difference was -0.37 SMD. Serious adverse events were analysed as relative risks. METHODS: Two reviewers independently extracted relevant data and assessed the risk of bias of trials using the Cochrane risk of bias tool. The predefined main analysis was based only on large, placebo controlled trials with ≥100 participants per group. Summary results were obtained through a random effects meta-analysis model. Cumulative meta-analysis and trial sequential analysis under a random effects model were also performed. RESULTS: 169 trials provided data on 21 163 randomised participants. Evidence of small study effects and publication biases was observed for pain and function (Egger's tests with P<0.001 and asymmetric funnel plots). Twenty four large, placebo controlled trials (8997 randomised participants) included in the main analysis of pain indicated that viscosupplementation was associated with a small reduction in pain intensity compared with placebo (SMD -0.08, 95% confidence interval -0.15 to -0.02), with the lower bound of the 95% confidence interval excluding the minimal clinically important between group difference. This effect corresponds to a difference in pain scores of -2.0 mm (95% confidence interval -3.8 to -0.5 mm) on a 100 mm visual analogue scale. Trial sequential analysis for pain indicated that since 2009 there has been conclusive evidence of clinical equivalence between viscosupplementation and placebo. Similar conclusions were obtained for function. Based on 15 large, placebo controlled trials on 6462 randomised participants, viscosupplementation was associated with a statistically significant higher risk of serious adverse events than placebo (relative risk 1.49, 95% confidence interval 1.12 to 1.98). CONCLUSION: Strong conclusive evidence indicates that viscosupplementation leads to a small reduction in knee osteoarthritis pain compared with placebo, but the difference is less than the minimal clinically important between group difference. Strong conclusive evidence indicates that viscosupplementation is also associated with an increased risk of serious adverse events compared with placebo. The findings do not support broad use of viscosupplementation for the treatment of knee osteoarthritis. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021236894.

A Japanese single-center experience of the efficacy and safety of asfotase alfa in pediatric-onset hypophosphatasia.

BACKGROUND: Hypophosphatasia (HPP) is a rare inherited metabolic disorder caused by mutations in the ALPL gene, which encodes tissue nonspecific alkaline phosphatase. The severity of HPP is widely diverse from the perinatal form to the adult mild form. The former represents the most severe form and was earlier associated with high mortality due to pneumonia which was caused by severe hypomineralization of the bones-such as chest deformity and fractured ribs-and muscle weakness. Enzyme replacement therapy using asfotase alfa (AA) was approved in 2015 in Japan for treating patients with HPP and has improved their pulmonary function and life prognosis. There are several practical and ethical challenges related to using orphan drugs for a rare disorder in a publicly funded healthcare system. Sharing experiences about their application is essential towards formulating guidelines to assist clinicians with decisions about their initiation and withdrawal. We report the details of AA experience in ten cases of pediatric-onset HPP in nine families from January 2015 to November 2019 (median [interquartile range] age 11.0 [7.6-12.5] years; 60% male). This is a study of a single-center cohort describing the clinical course of patients with HPP, mainly consisting of the mild childhood form of HPP, treated with AA in Japan. RESULTS: One case of perinatal form of HPP, two cases of benign prenatal form, and seven cases of childhood form were observed. The most common symptom at onset was pain. All patients had low serum alkaline phosphatase levels as compared to the age-matched reference range before the commencement of AA. All HPP patients seem to have responded to AA treatment, as evidenced by pain alleviation, increased height standard deviation, improvement in respiratory condition and 6-min walk test result improvement, disappearance of kidney calcification, alleviation of fatigue, and/or increases in bone mineralization. There were no serious adverse events, but all patients had an injection site reaction and skin changes at the injection sites. Genetic analysis showed that eight out of ten patients had compound heterozygosity. CONCLUSIONS: AA may be effective in patients with mild to severe pediatric-onset forms of HPP.

Opioid prescribing among new users for non-cancer pain in the USA, Canada, UK, and Taiwan: A population-based cohort study.

BACKGROUND: The opioid epidemic in North America has been driven by an increase in the use and potency of prescription opioids, with ensuing excessive opioid-related deaths. Internationally, there are lower rates of opioid-related mortality, possibly because of differences in prescribing and health system policies. Our aim was to compare opioid prescribing rates in patients without cancer, across 5 centers in 4 countries. In addition, we evaluated differences in the type, strength, and starting dose of medication and whether these characteristics changed over time. METHODS AND FINDINGS: We conducted a retrospective multicenter cohort study of adults who are new users of opioids without prior cancer. Electronic health records and administrative health records from Boston (United States), Quebec and Alberta (Canada), United Kingdom, and Taiwan were used to identify patients between 2006 and 2015. Standard dosages in morphine milligram equivalents (MMEs) were calculated according to The Centers for Disease Control and Prevention. Age- and sex-standardized opioid prescribing rates were calculated for each jurisdiction. Of the 2,542,890 patients included, 44,690 were from Boston (US), 1,420,136 Alberta, 26,871 Quebec (Canada), 1,012,939 UK, and 38,254 Taiwan. The highest standardized opioid prescribing rates in 2014 were observed in Alberta at 66/1,000 persons compared to 52, 51, and 18/1,000 in the UK, US, and Quebec, respectively. The median MME/day (IQR) at initiation was highest in Boston at 38 (20 to 45); followed by Quebec, 27 (18 to 43); Alberta, 23 (9 to 38); UK, 12 (7 to 20); and Taiwan, 8 (4 to 11). Oxycodone was the first prescribed opioid in 65% of patients in the US cohort compared to 14% in Quebec, 4% in Alberta, 0.1% in the UK, and none in Taiwan. One of the limitations was that data were not available from all centers for the entirety of the 10-year period. CONCLUSIONS: In this study, we observed substantial differences in opioid prescribing practices for non-cancer pain between jurisdictions. The preference to start patients on higher MME/day and more potent opioids in North America may be a contributing cause to the opioid epidemic.