Characterization of Codeine Treatment Responders Among Patients with Refractory or Unexplained Chronic Cough: A Prospective Real-World Cohort Study.

PURPOSE: Codeine is a narcotic antitussive often considered for managing patients with refractory or unexplained chronic cough. This study aimed to evaluate the proportion and characteristics of patients who responded to codeine treatment in real-world practice. METHODS: Data from the Korean Chronic Cough Registry, a multicenter prospective cohort study, were analyzed. Physicians assessed the response to codeine based on the timing and degree of improvement after treatment initiation. Follow-up assessments included the Leicester Cough Questionnaire and cough severity visual analog scale at six months. In a subset of subjects, objective cough frequency was evaluated following the initiation of codeine treatment. RESULTS: Of 305 patients, 124 (40.7%) responded to treatments based on anatomic diagnostic protocols, while 181 (59.3%) remained unexplained or refractory to etiological treatments. Fifty-one subjects (16.7%) were classified as codeine treatment responders (those showing a rapid and clear response), 57 (18.7%) as partial responders, and 62 (20.3%) as non-responders. Codeine responders showed rapid improvement in objective cough frequency and severity scores within a week of the treatment. At 6 months, responders showed significantly improved scores in cough scores, compared to non-responders. Several baseline parameters were associated with a more favorable treatment response, including older age, non-productive cough, and the absence of heartburn. CONCLUSIONS: Approximately 60% of chronic cough patients in specialist clinics may require antitussive drugs. While codeine benefits some, only a limited proportion (about 20%) of patients may experience rapid and significant improvement. This underscores the urgent need for new antitussive drugs to address these unmet clinical needs.

Opt-in versus universal codeine provision for medical abortion up to 10 weeks of gestation at British Pregnancy Advisory Service: a cross-sectional evaluation.

OBJECTIVE: To assess patient experiences of pain management during medical abortion up to 10 weeks' gestation with opt-in versus universal codeine provision. METHODS: We invited patients who underwent medical abortion up to 10 weeks of gestation to participate in an online, anonymous, English-language survey from November 2021 to March 2022. We performed ordinal regression analyses to compare satisfaction with pain management (5-point Likert scale) and maximum abortion pain score (11-point numerical rating scale) in the opt-in versus universal codeine provision groups. RESULTS: Of 11 906 patients invited to participate, 1625 (13.6%) completed the survey. Participants reported a mean maximum pain score of 6.8±2.2. A total of 1149 participants (70.7%) reported using codeine for pain management during their abortion. Participants in the opt-in codeine provision group were significantly more likely to be satisfied with their pain management than those in the universal group (aOR 1.48, 95% CI 1.12 to 1.96, p<0.01). Maximum abortion pain scores were lower on average among the opt-in codeine provision group (OR 0.80, 95% CI 0.66 to 0.96, p=0.02); however, this association was not statistically significant in the model adjusted for covariates (aOR 0.85, 95% CI 0.70 to 1.03, p=0.09). CONCLUSION: Our findings suggest that patients have a better experience with pain management during medical abortion when able to opt-in to codeine provision following counselling versus receiving this medication routinely.

Older Adult-Onset of Inflammatory Bowel Diseases Is Associated With Higher Utilization of Analgesics: A Nationwide Cohort Study.

INTRODUCTION: Patients with inflammatory bowel diseases (IBD) commonly require analgesic medications to treat pain, which may be associated with complications. We examined trends of analgesic use according to age at IBD onset. METHODS: This nationwide cohort study included adults diagnosed with IBD between 1996 and 2021 in Denmark. Patients were stratified according to their age at IBD onset: 18-39 years (young adult), 40-59 years (adult), and older than 60 years (older adult). We examined the proportion of patients who received prescriptions for analgesic medications within 1 year after IBD diagnosis: strong opioids, tramadol, codeine, nonsteroidal anti-inflammatory drugs, and paracetamol. Multivariable logistic regression analysis was performed to examine the association between age at IBD onset and strong opioid prescriptions and the composite of strong opioid/tramadol/codeine prescriptions. RESULTS: We identified 54,216 adults with IBD. Among them, 25,184 (46.5%) were young adults, 16,106 (29.7%) were adults, and 12,926 (23.8%) were older adults at IBD onset. Older adults most commonly received analgesic prescriptions of every class. Between 1996 and 2021, strong opioid, tramadol, and codeine prescriptions were stable, while paracetamol prescriptions increased and nonsteroidal anti-inflammatory drug prescriptions decreased. After multivariable logistic regression analysis, older adults had higher adjusted odds of receiving strong opioid prescriptions (adjusted odds ratio 1.95, 95% confidence interval 1.77-2.15) and the composite of strong opioid/tramadol/codeine prescriptions (adjusted odds ratio 1.93, 95% confidence interval 1.81-2.06) within 1 year after IBD diagnosis compared with adults. DISCUSSION: In this nationwide cohort, older adults most commonly received analgesic prescriptions within 1 year after IBD diagnosis. Additional research is needed to examine the etiology and sequelae of increased analgesic prescribing to this demographic.

Use of opioids among pregnant women 1997-2016: A Danish drug utilization study.

OBJECTIVE: Use of opioids in pregnancy is of concern yet little is known on opioid prescription patterns in Denmark. The aim of this drug utilization study was to describe prescription patterns for opioids during pregnancy in Denmark from 1997 to 2016. STUDY DESIGN: Using the nationwide health care registers, we obtained information on all women with a registered pregnancy in the period 1 January 1997 to 31 December 2016. Opioids were grouped in four: opioids (N02A except codeines), opioid dependency medications (N07BC), cough medications (R05DA except codeines), and codeines (N02AJ06, N02AJ07, N02BA75, and R05DA04). We used logistic regression analyses to identify factors associated with opioid use in pregnancy and cumulative oral morphine equivalent (OMEQ) to estimate volume of use in pregnancy. RESULTS: Prescription patterns were similar for women with live births, non-live births, and terminations. Total use of opioids among women with live born deliveries remained stable at 19.8 per 1000 pregnancies from 1997 to 2016. Codeine use declined from 2008 onwards, while use of other opioids increased from 2007 onwards. This was dominated by a threefold increase in tramadol use (2.0-7.6 per 1000 pregnancies with live births). Codeine was the most used opioid, followed by tramadol and codeine combined with paracetamol. The number of women, who used opioids before pregnancy and continued into their pregnancy, was reduced as the pregnancy progressed. The cumulative oral morphine equivalent during pregnancy was stable until 2007, after which, use prior to pregnancy and during the first two trimesters increased. The odds ratios for opioid use were higher in pregnancies of women of lower socioeconomic status or older age. For live births, odds ratios for opioid use in pregnancy were higher among women with obesity or smoking. CONCLUSIONS: Overall use of opioids was stable from 2007 to 2016. This covers a decline in the use of codeine, but a 3-fold increase in tramadol. The number of pregnant women who continued use throughout pregnancy decreased, while OMEQ among persistent users increased. The real-world data suggest an unmet need of specific focus in local Danish Outpatient Clinics and Multidisciplinary Pain Centers both pre-conceptionally and during pregnancy.

Opioid use and COVID-19: a secondary analysis of the impact of relaxation of methadone take-home dosing guidelines on use of illicit opioids.

Background: An exemption to existing U.S. regulation of methadone maintenance therapy after the onset of the COVID-19 pandemic permitted increased take-home doses beginning March 2020.Objectives: We assessed the impact of this exemption on opioid use.Methods: A pre/post study of 187 clients recruited from an OTP who completed a survey and consented to share their urine drug testing (UDT) data. Use of fentanyl, morphine, hydromorphone, codeine, and heroin was assessed via UDT. Receipt of take-home methadone doses was assessed from clinic records for 142 working days pre- and post-COVID exemption. Analysis was conducted using a linear regression model to assess the association between increased take-home doses and use of illicit opioids.Results: In the pre- vs. post-COVID-19 SAMHSA exemption periods, 26.2% vs. 36.3% of UDTs were positive for 6-acetylmorphine respectively, 32.6% vs. 40.6% positive for codeine, 34.2% vs 44.2% positive for hydromorphone, 39.5% vs. 48.1% positive for morphine, 8.0% vs. 14.4% positive for fentanyl (p-value < .001). However, in the unadjusted descriptive data, when grouped by change in substance use, those clients who experienced a decrease in the use of morphine, codeine, and heroin post-COVID-19 were given significantly more take-home doses than the groups that had no change or an increase in the use of these substances. In the adjusted model, there was no significant relationship between change in opioid use and increased receipt of take-home methadone doses.Conclusions: Although take-home doses post-COVID-19 nearly doubled, this increase was not associated with a significant change in use of illicit opioids.

Pharmacokinetics and effects of codeine in combination with acetaminophen on thermal nociception in horses.

Codeine and acetaminophen in combination have proven to be an effective analgesic treatment for moderate-to-severe and postoperative pain in humans. Studies have demonstrated that codeine and acetaminophen, when administered as sole agents, are well tolerated by horses. In the current study, we hypothesized that administration of the combination of codeine and acetaminophen would result in a significant thermal antinociceptive effect compared with administration of either alone. Six horses were administered oral doses of codeine (1.2 mg/kg), acetaminophen (20 mg/kg), and codeine plus acetaminophen (1.2 mg/kg codeine and 6-6.4 mg/kg acetaminophen) in a three-way balanced crossover design. Plasma samples were collected, concentrations of drug and metabolites determined via liquid chromatography-mass spectrometry, and pharmacokinetic analyses were performed. Pharmacodynamic outcomes, including effect on thermal thresholds, were assessed. Codeine Cmax and AUC were significantly different between the codeine and combination group. There was considerable inter-individual variation in the pharmacokinetic parameters for codeine, acetaminophen, and their metabolites in horses. All treatments were well tolerated with minimal significant adverse effects. An increase in the thermal threshold was noted at 1.5 and 2 h, from 15 min through 6 h and 0.5, 1, 1.5, and 3 h in the codeine, acetaminophen, and combination groups, respectively.

[Efficacy of compound pholcodine syrup and compound codeine phosphate oral solution on lung cancer-related cough].

Objective: To assess the clinical efficacy of compound pholcodine syrup and compound codeine phosphate oral solution on lung cancer-related cough. Methods: A total of 60 patients diagnosed with middle-advanced stage lung cancer and had lung cancer-related cough in the Department of Geriatric Oncology of Chongqing University Cancer Hospital from January to May 2022 were prospectively enrolled. According to the random number table method, the patients were divided into two groups: observation group and control group. The observation group [n=30, with 21 males and 9 females, and aged (62.3±10.4) years] received compound pholcodine syrup treatment, while the control group [n=30, with 21 males and 9 females, and aged (62.0±8.1) years] received compound codeine phosphate oral solution treatment. The dosage of the two drugs was 15 ml each time, 3 times a day, and the treatment course was 5 days. The antitussive effectiveness, cough severity and quality of life (Leicester Cough Questionnaire in Mandarin-Chinese scale) were observed and compared between the two groups 3 days and 5 days after the treatment. Results: All 60 patients completed the study. Both regimens were effective in controlling lung cancer-related cough. After 3 days treatment, the antitussive effective rate of the observation group and the control group was 83.3% (25/30) and 73.3% (22/30), respectively, with no statistically significant difference (P=0.347). Likewise, after 5 days treatment, the antitussive effective rate of observation group and control group was 90.0% (27/30) and 86.6% (26/30), respectively, with no statistically significant difference (P=0.687). There was no statistically significant difference in the cough severity between observation group [moderate and severe cough: 56.7% (17/30)] and control group [moderate and severe cough: 67.7% (20/30)] (P=0.414). After 3 days treatment, cough symptoms were relieved in both groups. Patients with mild cough accounted for 73.3% (22/30) in the observation group and 56.7% (17/30) in the control group, and the difference was not statistically significant (P=0.331). Moreover, after 5 days treatment, there was also no significant difference in mild cough between observation group [86.7% (26/30)] and control group [66.7% (20/30)] (P=0.067). Meanwhile, there were no significant differences in the physiological score, psychological score, social score and total score of the Leicester Cough Questionnaire in Mandarin-Chinese scale before the treatment, after 3 days and 5 days treatment between the two groups (all P>0.05). The incidence of both xerostomia and constipation in the observation group was 0, which was lower than those of the control group [20.0% (6/30) and 20.0% (6/30)] (both P<0.05). Conclusions: Both compound pholcodine syrup and compound codeine phosphate oral solution are effective in treating lung cancer-related cough with similar antitussive effectiveness. Compound pholcodine syrup has a lower incidence of xerostomia and constipation than control group, with a better safety profile.

Analgesic efficacy of naproxen-codeine, naproxen+dexamethasone, and naproxen on myofascial pain: A randomized double-blind controlled trial.

OBJECTIVE: To assess the effects of naproxen sodium-codeine phosphate, naproxen sodium-dexamethasone, and naproxen sodium on myofascial pain. METHODS: This randomized, double-blind prospective clinical study was conducted with patients who applied with the complaint of pain in the temporomandibular region. A total of 169 patients were randomly divided into four groups and received the following treatments: Group A: naproxen sodium 550 mg; Group B: naproxen sodium 550 mg + codeine phosphate 30 mg; Group C: naproxen sodium 550 mg + single-dose dexamethasone 8 mg, and Group D: paracetamol 500 mg. RESULTS: Of the patients, 132 were female, and 37 were male, with a mean age of 27.04 ± 10.56 (18-69 years). Analgesic efficiency of the naproxen sodium-codeine phosphate group was the most effective at the 2nd week and 4th week (p < 0.05). CONCLUSION: Naproxen sodium-codeine phosphate might be preferred as an analgesic in similar cases with severe myofascial pain.

A retrospective analysis of the impact of Michigan's opioid prescribing legislation on discharge opioid prescribing at a single institution.

This study sought to determine if there were any changes in opioid prescribing habits of providers at a single institution after the implementation of legislation to increase opioid prescribing regulations. Our study demonstrated a 39.5 percent decrease in overall morphine milligram equivalent (MME) prescribed the year after the laws took effect when compared with the year prior. It is clear that these laws have been effective in decreasing the number of opioids prescribed at discharge from Mercy Health Grand Rapids. INTRODUCTION: Opioid use disorder has become an epidemic with approximately 130 people dying every day in the United States due to prescription and illegal opioid overdoses. In December 2017, the Michigan legislature ratified a package of 10 acts to address a variety of problems through several layers of regulations including more restrictive prescribing rules, which took effect in June 2018. OBJECTIVE: To evaluate the impact of legislation on the opioid prescribing habits of providers who discharged patients from a community-based academic teaching hospital. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was performed using data from a community-based academic teaching hospital with 303 beds, a medical ICU, labor and delivery unit, and a 42-room emergency department. All patients discharged from in-patient or observation status in the 12 months before and after June 1, 2018 were included. MAIN OUTCOMES AND MEASURES: The primary outcome was MMEs of opioids prescribed at discharge before (June 1, 2017 to May 31, 2018) and after (June 1, 2018 to May 31, 2019) legislation. Medications included morphine, hydrocodone, oxycodone, fentanyl, methadone, hydromorphone, tramadol, codeine, and meperidine. RESULTS: There were 17,227 patients discharged during the first 12-month period and 15,855 patients discharged in the second 12-month period. There were 14,064 new opioid prescriptions in total during these time periods. Total MME prescribed during the study period showed a 39.5 percent decrease from pre- (2,268,460 MME) to post-legislation (1,372,424 MME), while average MMEs/discharge significantly decreased (135.1 ± 321.2 vs. 87.6 ± 187.4; p < 0.001). Total pill/patch count decreased by almost 40 percent. For patients who were prescribed opioids, average MME/discharge showed significant decline after legislation implementation (309.6 ± 427.1 vs. 212.2 ± 242.1; p < 0.001). Average daily MME/patient prescribed an opioid remained similar between the time periods (52.4 ± 37.0 vs. 51.6 ± 35.0; p = 0.21). Significant reductions (p < 0.05) were seen in MMEs for each individual medication with the exception of acetaminophen-codeine and methadone. CONCLUSIONS AND RELEVANCE: Our results indicate that the legislation implemented in Michigan to regulate opioid prescriptions was associated with a reduction in opioids prescribed to patients discharged from a community-based academic teaching hospital.

Tramadol and Codeine Stacking/Boosting Dose Exposure Induced Neurotoxic Behaviors, Oxidative Stress, Mitochondrial Dysfunction, and Neurotoxic Genes in Adolescent Mice.

In spite of the increasing epidemic of pharmaceutical opioids (codeine and tramadol) misuse and abuse among the adolescents, little is known about the neurotoxic consequences of the widespread practice of tramadol and codeine abuse involving increasing multiple doses across days, referred to as stacking and boosting. Hence, in this study, we replicated stacking and boosting doses of tramadol, codeine alone, or in combination on spontaneous motor activity and cognitive function in adolescent mice and adduced a plausible mechanism of possible neurotoxicity. Ninety-six adolescent mice were randomly distributed into 4 groups (n = 24 per group) and treated thrice daily for 9 days with vehicle, tramadol (20, 40, or 80 mg/kg), codeine (40, 80, or 160 mg/kg), or their combinations. Exposure of mice to tramadol induced hyperactivity and stereotypic behavior while codeine exposure caused hypoactivity and nootropic effect but tramadol-codeine cocktail led to marked reduction in spontaneous motor activity and cognitive function. In addition, tramadol, codeine, and their cocktail caused marked induction of nitroso-oxidative stress and inhibition of mitochondrial complex I activity in the prefrontal cortex (PFC) and midbrain (MB). Real-time PCR expression profiling of genes encoding neurotoxicity (RT) showed that tramadol exposure upregulate 57 and downregulate 16 neurotoxic genes, codeine upregulate 45 and downregulate 25 neurotoxic genes while tramadol-codeine cocktail upregulate 52 and downregulate 20 neurotoxic genes in the PFC. Findings from this study demonstrate that the exposure of adolescents mice to multiple and increasing doses of tramadol, codeine, or their cocktail lead to spontaneous motor coordination deficits indicative of neurotoxicity through induction of oxidative stress, inhibition of mitochondrial complex I activity and upregulation of neurotoxicity encoding genes in mice.

Comparative risk-benefit profiles of weak opioids in the treatment of osteoarthritis: a network meta-analysis of randomized controlled trials.

BACKGROUND: Despite their poor tolerance, weak opioids are still the most commonly-prescribed medicine for osteoarthritis (OA)-related pain. The objective of this network meta-analysis was to comparatively examine the efficacy and safety of weak opioids in OA treatment. METHODS: Databases including PubMed, Embase, Cochrane Library and Web of Science were searched from inception to 4 April 2022 to retrieve randomized controlled trials (RCTs) comparing weak opioids with placebo or between one another in OA patients. Bayesian network meta-analysis was performed on the following outcomes of interest, namely the change-from-baseline score in pain relief, gastrointestinal (GI) adverse events (AEs), central nervous system (CNS) AEs, and total number of AEs (i.e. the number of subjects experiencing any AE for at least once) during follow-up. The surface under the cumulative ranking curve (SUCRA) was used to rank the effectiveness of each treatment and identify the best treatment. RESULTS: A total of 14 RCTs invoving four types of weak opioids were included in this meta-analysis. Compared to placebo, tramadol (standardized mean difference [SMD] = -0.34, 95% credible interval [CrI]: -0.53 to -0.18) and codeine (SMD = -0.39, 95% CrI: -0.79 to -0.04) were effective for pain relief, but involved a higher risk of GI AEs, CNS AEs and total number of AEs. Dextropropoxyphene demonstrated a significantly lower risk of GI AEs (OR = 0.28, 95%CrI: 0.17 to 0.51), CNS AEs (OR = 0.29, 95%CrI: 0.11 to 0.78) and total number of AEs (OR = 0.35, 95%CrI: 0.15 to 0.82) compared to codeine. Dihydrocodeine had a better safety profile in CNS AEs (SUCRA = 64.8%) and total number of AEs (SUCRA = 66.6%). CONCLUSIONS: The results of the present study confirmed that tramadol and codeine were effective drugs for the treatment of OA, but involved considerable safety issues. Dextropropoxyphene and dihydrocodeine exhibited a relatively good safety profile but their efficacy still warrant further investigation.

Assessing local California trends in emergency physician opioid prescriptions from 2012 to 2020: Experiences in a large academic health system.

OBJECTIVES: There has been increased focus nationally on limiting opioid prescriptions. National data demonstrates a decrease in annual opioid prescriptions among emergency medicine physicians. We analyzed data from 2012 to 2020 from a large academic health system in California to understand trends in opioid prescribing patterns for emergency department (ED) discharged patients and assessed the potential impact of two initiatives at limiting local opioid prescriptions. METHODS: In 2012-2020, monthly ED visit data was used to evaluate the total number of outpatient opioid prescriptions and percent of ED visits with opioid prescriptions (as primary outcomes). Descriptive statistics, graphic representation, and segmented regression with interrupted times series were used based on two prespecified time points associated with intensive local initiatives directed at limiting opioid prescribing1) comprehensive emergency medicine resident education and 2) electronic health record (EHR)-based intervention. RESULTS: Between March 2012 and July 2020, a total of 41,491 ED discharged patients received an opioid prescription. The three most commonly prescribed drugs were hydrocodone (84.1%), oxycodone (10.8%), and codeine (2.8%). After implementing comprehensive emergency medicine resident education, the total number of opioid prescriptions, the percentage of opioid prescriptions over total ED visit numbers and the total tablet number showed decreasing trends (p's ≤ 0.01), in addition to the natural (pre-intervention) decreasing trends. In contrast, later interventions in the EHR tended to show attenuated decreasing trends. CONCLUSIONS: From 2012 to 2020, we found that total opioid prescriptions decreased significantly for discharged ED patients. This trend is seen nationally. However, our specific interventions further heightened this downward trend. Evidence-based legislation, policy changes, and educational initiatives that impact prescribing practices should guide future efforts.

Pain Relief with Combination Acetaminophen/Codeine or Ibuprofen following Third-Molar Extraction: A Systematic Review and Meta-Analysis.

OBJECTIVE: The purpose of our study was to perform a systematic review and meta-analysis of randomized, blinded, placebo-controlled studies that, following third-molar extraction, utilized either a combination of acetaminophen (600 mg) with codeine (60 mg) or ibuprofen (400 mg) for pain management. DESIGN: We searched PubMed, and the trial registry ClinicalTrials.gov databases with the keywords "molar or molars," "tooth or teeth," "extraction," and "pain." Selected studies were: (1) randomized, blinded, placebo controlled, (2) utilized either a single-dose combination acetaminophen (600 mg) with codeine (60 mg) (A/C) or ibuprofen, and (3) recorded standardized pain relief (PR) at 6 hours, or summed total pain relief over 6 hours (TOTPAR6). Of the 2,949 articles that were identified, 79 were retrieved for full-text analysis, and 20 of these studies met our inclusion criteria. RESULTS: For A/C, the weighted, standardized mean difference (SMD) for TOTPAR6 was 0.796 (95% confidence interval [CI], 0.597-0.995), P < .001, and for PR at 6 hours, the SMD was 0.0186 (0.007 to 0.378; P = .059), whereas for ibuprofen the SMD for TOTPAR6 was 3.009 (1.283 to 4.735; P = .001), and for PR at 6 hours, the SMD was 0.854 (95% CI, 0.712-0.996; P < .001). A SMD of 0.8 or larger is indicative of a large effect. CONCLUSIONS: Our data indicate that single dose of ibuprofen (400 mg) is an effective pain reducer for post third molar extraction pain.

Pain Management Following Otological Surgery: A Prospective Study of Different Strategies.

OBJECTIVES: The aim of this study was to prospectively assess pain and associated analgesic consumption after otological surgery comparing two prescription patterns. STUDY DESIGN: A prospective nonrandomized consecutive cohort study. METHODS: 125 adult patients undergoing ambulatory otologic surgery-cochlear implantation and endaural middle ear surgery, were assigned (according to surgeon's preference) and prospectively studied in two arms: 1) acetaminophen 500 mg + ibuprofen 400 mg; 2) acetaminophen 500 mg + codeine 30 mg. Pain levels, medication dose, disposal patterns of opioids, and suspected side effects were evaluated. RESULTS: All patients reported mild to moderate pain. There was a statistically significant reduction of pain from day to day, which was on average 0.26 lower than the day before. Sufficient pain control could be achieved with both drug regimens with no significant difference in pain levels. Only 50% of patients who were prescribed opioids used them. Additionally, the median tablet intake was 3 tablets while 10 to 20 tablets were prescribed. The majority of patients (97%) did not dispose of these drugs safely. CONCLUSION: Adequate analgesia was achieved in both arms of this study. Pain control following otologic surgery with a combination of acetaminophen and nonsteroidal anti-inflammatory drugs is recommended unless contraindications or chronic opioid use are present. If opioids such as codeine (30 mg) are prescribed, the amount should be reduced as low as possible, such as five tablets, based on our studied population. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:204-211, 2022.

A prospective cohort study evaluating the impact of upscheduling codeine in Australia among frequent users of codeine.

AIM: To evaluate and document the impacts of re-scheduling codeine to a prescription-only medication in Australia in February 2018. DESIGN: Prospective cohort study. Participants completed an on-line survey with a range of outcome measures at four time-points, once before codeine was re-scheduled (November 2017) and three times after the event: 1 month after (February 2018), 4 months after (June 2018) and 12 months after (February 2019). SETTING: Australia. PARTICIPANTS: Participants were 260 Australians aged 18 years and above who reported regular over-the-counter (OTC) codeine use and, at the time of the study, were not engaged in treatment for codeine dependence. MEASUREMENTS: Survey measures included estimates of daily average codeine use (mg) and overall daily average opioid use [calculated using an oral morphine equivalent daily dose (OMEDD, mg)], opioid use disorder with regard to codeine use (using a modified Alcohol Use Disorder and Associated Disabilities Interview Schedule-IV), pain and pain self-efficacy, anxiety and depression and health service use. FINDINGS: A reduction in total daily codeine use (mg) from 64.3 mg [95% confidence interval (CI) = 46.7-81.9] in November 2017 (baseline) to 27.6 mg (95% CI = 19.2-36.0) in February 2019 (final time-point) was observed. A decline in the proportion of participants who met criteria for an opioid use disorder was also evident, with 51.2% (n = 133) at baseline relative to 33.3% (n = 58) at the 12-month follow-up. This study had an overall participant retention rate of 67% at the final time-point. CONCLUSION: Re-scheduling codeine in Australia has been accompanied by significant reductions in codeine use and prevalence rates of opioid use disorder in a cohort of individuals who regularly use the medication, without apparent adverse impacts on pain or measures of anxiety and depression.

Improving Opioid Stewardship in Pediatric Emergency Medicine.

OBJECTIVES: Poor opioid stewardship contributes to opioid misuse and adverse health outcomes. We sought to decrease opioid prescriptions in children 0 to 18 years treated for pain after fractures and cutaneous abscess drainage from 13.5% to 8%. Our secondary aims were to reduce opioid prescriptions written for >3 days from 41% to 10%, eliminate codeine prescriptions, increase safe opioid storage and disposal discharge instructions from 0% to 70%, and enroll all emergency department (ED) physicians in the state prescription drug monitoring program. METHODS: We implemented an intervention bundle on the basis of 4 key drivers at a pediatric ED: ED-wide education, changes in the electronic medical record, discharge resources, and process standardization. Two plan-do-study-act cycles were performed. Interventions included provider feedback on prescribing, safe opioid storage and disposal instructions, and streamlined electronic medical record functions. Run charts were used to analyze the effect of interventions on outcomes. Our balance measure was return ED or clinic visits for inadequate analgesia within 3 days. RESULTS: During the intervention period, 249 of 3402 (7.3%) patients with fractures and cutaneous abscesses were prescribed opioids. The percentage of opioid prescriptions >3 days decreased from 41% to 13.2% (P < .0001), codeine prescription dropped from 1.1% to 0% (P = .09), opioid discharge instructions increased 0% to 100% (P < .0001), and all physicians enrolled in the prescription drug monitoring program. There was no change in return visits for uncontrolled analgesia compared with the baseline (P = .79). CONCLUSIONS: A comprehensive opioid stewardship program can improve opioid prescribing practices of ED physicians and deliver information on safe storage and disposal of prescription opioids with a negligible effect on return visits for uncontrolled pain.

Opioid Analgesic Prescription in French Children: A National Population-Based Study.

Codeine use was restricted in 2013 and is currently contraindicated for children below the age of 12 years. We examined how the prescription of opioid analgesics in children in France evolved between 2012 and 2018. Our population-based study from the SNIIRAM database (National System of Health Insurance Inter-Regime Information) was designed to determine trends in opioid prescription from 2012 to 2018 in all French children. The number of children who received at least one opioid prescription gradually declined from 452,665 in 2012 (347.5 children per 10,000) to 169,338 in 2018 (130.3 children per 10,000). This decrease was especially marked for codeine (36 children per 10,000 in 2018 vs. 308.5 children per 10,000 in 2012), whereas the number of tramadol prescriptions increased by 171% in 2018 (94.6 children per 10,000). Despite the increase, strong opioids still formed only a small proportion of prescriptions (2.6 children per 10,000 given opioids in 2018). Overall opioid prescriptions in French children dramatically decreased between 2012 and 2018, probably owing to restrictions on the use of codeine. Codeine has been partly replaced by tramadol. Morphine is still probably underused. This suggests that opioids are being used less often for pain management in children.

Effectiveness of Oxycodone Hydrochloride (Strong Opioid) vs Combination Acetaminophen and Codeine (Mild Opioid) for Subacute Pain After Fractures Managed Surgically: A Randomized Clinical Trial.

Importance: Patients with a surgically managed fracture are commonly discharged from the hospital with a strong opioid prescription, but limited evidence exists to support this practice. Objective: To test the hypothesis that strong opioids provide greater analgesia than mild opioids over the first week postdischarge from hospital after fracture surgical treatment. Design, Setting, and Participants: This double-blind, superiority, randomized clinical trial was conducted at a single-center, major trauma hospital in Sydney, Australia. Participants were inpatients who had sustained an acute nonpathological facture of a long bone or the pelvis, patella, calcaneus, or talus who were treated with surgical fixation and enrolled from July 27, 2016, to August 22, 2017. Data were analyzed from June through October 2018. Interventions: Initiation at discharge of oxycodone hydrochloride 5 mg of 10 mg (ie, 1 or 2 tablets) or combination acetaminophen and codeine 500 mg and 8 mg or 1000 mg and 16 mg (ie, 1 or 2 tablets) 4 times daily for a maximum duration of 3 weeks. Main Outcomes and Measures: The primary outcome was the mean of daily pain scores collected during week 1 of treatment measured using the Numerical Pain Rating Scale (NRS). Participants were asked to rate their mean pain over the previous 24 hours daily using an NRS score from 0 to 10, with 0 representing no pain and 10 representing the worst pain imaginable. The key secondary outcomes were EuroQol 5-Dimension 5-Level Questionnaire (EQ-5D-5L) responses, worst pain, medication adverse events, global perceived effect, and return to work. Results: A total of 120 patients with 1 or more acute orthopedic fractures requiring surgical fixation were randomized, including 59 patients in the strong-opioid group (43 [72.9%] men; mean [SD] age, 36.0 [14.1] years; mean oral morphine equivalent for days 1-7 of 32.9 mg) and 61 patients in the mild opioid group (47 [77.1%] men; mean [SD] age, 38.2 [13.5] years; mean oral morphine equivalent for days 1-7 of 5.5 mg). From days 1 to 7 postdischarge, the mean daily NRS mean pain score was 4.04 (95% Cl, 3.67 to 4.41) in the strong opioid group and 4.54 (95% Cl, 4.17 to 4.90) in the mild opioid group. The between-group difference of the primary outcome was not statistically significant (-0.50 [95% Cl, -1.11 to 0.12]; P = .11) despite a 6-fold increased dose of opioids being delivered in the strong opioid group. Conclusions and Relevance: This study found that treatment with strong opioid medication subacutely was not superior to treatment with milder medication for treatment of pain among patients with surgically managed orthopedic fractures. These findings suggest that ongoing first-line strong opioid use after discharge from the hospital should not be supported. Trial Registration: Australia New Zealand Clinical Trial Registry No.: ACTRN12616000941460.

Analgesic effect of oral ibuprofen 400, 600, and 800 mg; paracetamol 500 and 1000 mg; and paracetamol 1000 mg plus 60 mg codeine in acute postoperative pain: a single-dose, randomized, placebo-controlled, and double-blind study.

PURPOSE: Effect size estimates of analgesic drugs can be misleading. Ibuprofen (400 mg, 600 mg, 800 mg), paracetamol (1000 mg, 500 mg), paracetamol 1000 mg/codeine 60 mg, and placebo were investigated to establish the multidimensional pharmacodynamic profiles of each drug on acute pain with calculated effect size estimates. METHODS: A randomized, double-blind, single-dose, placebo-controlled, parallel-group, single-centre, outpatient, and single-dose study used 350 patients (mean age 25 year, range 18 to 30 years) of homogenous ethnicity after third molar surgery. Primary outcome was sum pain intensity over 6 h. Secondary outcomes were time to analgesic onset, duration of analgesia, time to rescue drug intake, number of patients taking rescue drug, sum pain intensity difference, maximum pain intensity difference, time to maximum pain intensity difference, number needed to treat values, adverse effects, overall drug assessment as patient-reported outcome measure (PROM), and the effect size estimates NNT and NNTp. RESULTS: Ibuprofen doses above 400 mg do not significantly increase analgesic effect. Paracetamol has a very flat analgesic dose-response profile. Paracetamol 1000/codeine 60 mg gives similar analgesia as ibuprofen from 400 mg, but has a shorter time to analgesic onset. Active drugs show no significant difference in maximal analgesic effect. Other secondary outcomes support these findings. The frequencies of adverse effects were low, mild to moderate in all active groups. NNT and NTTp values did not coincide well with PROMs. CONCLUSION: Ibuprofen doses above 400 mg for acute pain offer limited analgesic gain. Paracetamol 1000 mg/codeine 60 mg is comparable to ibuprofen doses from 400 mg. Calculated effect size estimates and PROM in our study seem not to relate well as clinical analgesic efficacy estimators. TRIAL REGISTRATION: NCT00699114.