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.

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.

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.

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.

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.

CYP2D6 genotype and reduced codeine analgesic effect in real-world clinical practice.

Cytochrome P450 2D6 (CYP2D6) O-demethylates codeine to the active drug, morphine. However, the utility of testing for CYP2D6 metabolizer status in patients receiving codeine in real-world clinical practice is poorly defined. Using data from a DNA bank linked to de-identified electronic health records, we studied 157 patients with a baseline pain score higher than 4 (0-10 scale) who received codeine. Based on CYP2D6 genotyping, 69 were classified as poor/intermediate and 88 as normal/ultrarapid CYP2D6 metabolizers. Pain response was defined as a score of 4 or lower while receiving codeine. In a propensity-score adjusted model, poor/intermediate metabolizers had lower odds (OR = 0.35, p = 0.02) of achieving a pain response than normal/ultrarapid metabolizers. To discriminate between codeine responders and nonresponders, a score including CYP2D6 phenotype and clinical variables was built. The response rate was 38.5% among patients in the high, 17.3% in the intermediate, and 9.4% in the low-score groups, respectively (p = 0.001).

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.

Clinical Consumption of Compound Opioid Analgesics in China: A Retrospective Analysis of National Data 2015-2018.

Compound opioid analgesics (COA) are widely used for cancer pain relief, but few studies investigated the use of that. We aimed to report the characteristics and trend of COA consumption in different regions and health facilities in China. The procurement data of two types of COA, compound codeine phosphate (CCP) and oxycodone and acetaminophen (OAA), in all medical institutions of 20 provinces from 2015 to 2018 were used. Data were presented as defined daily dose for statistical purpose (SDDD) and expenditures per million inhabitants per day. The annual consumption of COA and ratio of two combinations were compared among regions and institutions. We found, during 2015-2018, COA consumption increased at an average rate of 7.32% in SDDD and 19.19% in expenditures, while OAA accounted for most of the consumption. Highest COA consumption appeared in Northern China, with 121.72 SDDD and 1689.87 RMB (2015), whereas the lowest COA consumption was only 11.28 SDDD appearing in Southern China. The ratio of OAA and CCP (in SDDD) was highest in Southern China (53.14 in 2018), whereas lowest in West North (0.37 in 2018). In terms of institutions, tertiary had the highest COA consumption, with 16.74 SDDD and 292.73 RMB (2018). The SDDD of OAA was 27.44 times of that of CCP in tertiary, while it was only 0.11 in primary. Overall, COA consumption is on an upward trend and different among regions and health institutions in either amount or types of COA. These findings call for establishment of COA management regulations.

Filled prescriptions for opioids among children and adolescents - A nationwide study from 2010 to 2018.

BACKGROUND: Prescribing opioids for children and adolescents should be reserved for advanced life-limiting diseases and moderate-to-severe acute pain. Pediatric codeine use is discouraged by several authorities, but the effects of these recommendations are not fully known. We investigated opioid utilization trends among 0-18-year-olds and characterized those who filled ≥1 opioid prescriptions, with emphasis on those who did so >3 times within a year. METHODS: The prevalence of filled opioid prescriptions among 0-18-year-old Norwegians in 2010-2018 (N = 77,942) was measured from nationwide healthcare registries. Characteristics, healthcare utilization, and other drug use of those who newly filled 1, 2-3, or >3 opioid prescriptions in 2011-2014 were compared to 2015-2018, excluding persons with cancer. RESULTS: From 2010 to 2018, the prevalence of opioid use decreased from 9.0 to 7.0 per 1000 persons. The largest decrease was among children <12 years, from 4.1 to 0.4 per 1000 persons, mainly due to decreasing codeine use. The proportion of those who filled >3 opioid prescriptions was 2.1% in 2011-2014 and 3.1% in 2015-2018. Those with >3 dispensations had a median of 4 contacts/year with secondary healthcare (interquartile range 2-7); the most frequent diagnoses indicated post-surgery follow-up. Most commonly dispensed other drugs were non-steroidal anti-inflammatory drugs. CONCLUSIONS: Opioid dispensations for the young have declined in recent years. Multiple opioid dispensations were rare and associated with frequent healthcare utilization. Reducing codeine is in line with recommendations, but the effects of decreased opioid use on the quality of pain management remain unknown.

Randomized Controlled Trials of Headache Treatments in Pregnancy: A Systematic Review.

OBJECTIVE: Headaches affect 88% of reproductive-aged women. Yet data are limited addressing treatment of headache in pregnancy. While many women experience improvement in pregnancy, primary and secondary headaches can develop. Consequently, pregnancy is a time when headache diagnosis can influence maternal and fetal interventions. This study was aimed to summarize existing randomized control trials (RCTs) addressing headache treatment in pregnancy. STUDY DESIGN: We searched PubMed, CINAHL, EMBASE, ClinicalTrials.gov, Cochrane Library, CINAHL, and SCOPUS from January 1, 1970 through June 31, 2019. Studies were eligible if they were English-language RCTs addressing treatment of headache in pregnancy. Conference abstracts and studies investigating postpartum headache were excluded. Three authors reviewed English-language RCTs addressing treatment of antepartum headache. To be included, all authors agreed each article to meet the following criteria: predefined control group, participants underwent randomization, and treatment of headache occurred in the antepartum period. If inclusion criteria were met no exclusions were made. Our systematic review registration number was CRD42019135874. RESULTS: A total of 193 studies were reviewed. Of the three that met inclusion criteria all were small, with follow-up designed to measure pain reduction and showed statistical significance. CONCLUSION: Our systematic review of RCTs evaluating treatment of headache in pregnancy revealed only three studies. This paucity of data limits treatment, puts women at risk for worsening headache disorders, and delays diagnosis placing both the mother and fetus at risk for complications.

Comparison between isolated and associated with codeine acetaminophen in pain control of acute apical abscess: a randomized clinical trial.

OBJECTIVES: The study aimed to compare the acetaminophen administration efficacy or its combination with codeine for pain control in acute apical abscesses cases. MATERIALS AND METHODS: Thirty-nine patients who sought emergency treatment in the Faculty of Dentistry of the Federal University of Rio Grande do Sul were included, all of them with acute apical abscess diagnosis. These patients were divided into two groups: acetaminophen group-prescription of acetaminophen (1000 mg) and acetaminophen-codeine group-prescription of acetaminophen (1000 mg) + codeine (30 mg), both with oral intake every 6 h for 3 days. The pain scores were recorded by the patients on their own at 6, 12, 24, 48, and 72 h after finishing clinical assistance, by filling a pain evolution journal, containing a visual analogue scale (VAS). Student t test was conducted to investigate different mean ages between groups 1 and 2. A comparison of weight and means of initial pain scores between groups was carried out using the Mann-Whitney U test. Chi-square test was performed to compare gender, affected tooth, education, initial swelling, and frequency of adverse effect between test and control groups. Mann-Whitney U test was applied to compare groups in the same period. Friedman's test was used to compare results from the same group over time. RESULTS: Both groups showed score reduction over time (P < 0.05). Paracetamol-codeine group showed significant pain score reduction at 48 h registers when compared to baseline and at 6 h scores (P < 0.05). Further, pain scores at 72 h were significantly lower, when compared to the baseline, at 6 h, and at 12 h scores (P < 0.05). Acetaminophen group showed significant pain score reduction observed at 72 h, when compared to the baseline and at 6 h scores (P < 0.05). There were no significant differences in pain score reduction over time between groups (P > 0.05). There was no difference between the groups regarding the frequency of adverse reactions (P > 0.05). CONCLUSION: Both medications were effective for pain control in acute apical abscess cases. The findings might have inferred in pain control of acute apical abscess associated pain in patients who used an antibiotic drug. External validity of the findings for acute apical abscess cases with no need for an antibiotic prescription is uncertain. CLINICAL RELEVANCE: This paper suggests acetaminophen 1000 mg can be used for pain control in the treatment of acute apical abscess associated with systemic manifestation.

We Need to Talk About Codeine: an Implementation Study to reduce the number of Emergency Department patients discharged on high-strength co-codamol using the Behaviour Change Wheel.

BACKGROUND: The crisis of prescription opioid addiction in the USA is well-documented. Though opioid consumption per capita is lower in the UK, prescribing has increased dramatically in recent decades with an associated increase in deaths from prescription opioid overdose. At one Scottish Emergency Department high rates of prescribing of take-home co-codamol (30/500 mg) were observed, including for conditions where opioids are not recommended by national guidelines. An Implementation Science approach was adopted to investigate this. METHODS: A Behaviour Change Wheel analysis suggested several factors contributing to high opioid prescribing: poor awareness of codeine addiction risk, poor knowledge of NICE (National Institute for Health and Care Excellence) guidelines on common painful conditions, mistaken assumptions about patient expectations and ready access to a large stock of take-home co-codamol. Based on this analysis a combined Education/Persuasion intervention was implemented over a 1-month period (January 2019) reaching 93% of prescribers. An Environmental Restructuring intervention was introduced at 4 months, and co-codamol prescriptions were monitored over a 12-month follow-up period. Unplanned re-attendances and complaints related to analgesia were monitored as balancing measures. RESULTS: The Education/Persuasion intervention was associated with a 59% reduction in co-codamol prescribing that was maintained over 12 months. The Environmental Restructuring intervention was not associated with any further reduction in prescribing. No increase in unplanned re-attendances occurred during the study period and no complaints were received relating to pain control. CONCLUSIONS: The increasing incidence of prescription opioid addiction in the UK suggests the need for all clinicians who write opioid prescriptions to re-evaluate their practice. This study suggests that knowledge of addiction risk and prescribing guidelines is poor among Emergency Department prescribers. We show that a rapid and sustained reduction in prescribing of take-home opioids is feasible in a UK Emergency Department, and that this reduction was not associated with any increase in unplanned re-attendances or complaints related to analgesia.

Evaluation of a state law on opioid-prescribing behaviour and the void affecting codeine-containing antitussive syrup.

BACKGROUND: Government opioid policies-such as the North Carolina Strengthen Opioid Misuse Prevention (STOP) Act-have aided in lowering the days' supply of opioid prescriptions. However, what effect do these laws have on codeine-containing antitussive syrup? We aimed to assess the effect of the North Carolina STOP Act on ED opioid prescriptions written for >5 days for acute pain/non-pain diagnoses and whether it had an effect on the prescribing of codeine-containing antitussive syrup. METHODS: A retrospective study of two emergency departments, with an average annual census of 70 000 and 22 000 patients, from January to August of 2017 and 2018. We applied logistic regression techniques to calculate the odds of an opioid prescription for >5 days. Opioid medication categories were formed to determine relational proportions. Two-tailed z-tests were used to test the difference in proportions. RESULTS: Our study included 5366 verifiable opioid prescriptions. The percentage of an opioid prescription for >5 days decreased by 3.3% (95% CI -1.8% to -4.7%, p<0.05) after the North Carolina STOP Act (9.8% to 6.5%; 95% CI 5.5% to 7.5%, p<0.05). There was no statistically significant change in the prescribing of codeine syrup for >5 days pre-STOP and post- STOP Act, respectively (91.5% and 90.4%; difference=-1.1%, p=0.83). CONCLUSION: The North Carolina STOP Act was associated with a reduction in the overall percentage of opioid prescriptions for >5 days for acute pain/non-pain diagnoses. However, there was no statistically significant effect on the prescribing of codeine-containing antitussive syrup.

Association of tramadol with risk of myocardial infarction among patients with osteoarthritis.

OBJECTIVE: Tramadol has been widely used among patients with osteoarthritis (OA); however, there is paucity of information on its cardiovascular risk. We aimed to examine the association of tramadol with risk of myocardial infarction (MI) among patients with OA. DESIGN: Among OA patients aged 50-90 years without history of MI, cancer, or opioid use disorder in The Health Improvement Network database in the United Kingdom (2000-2016), three sequential propensity-score matched cohort studies were assembled, i.e., (1) patients who initiated tramadol or naproxen (negative comparator); (2) patients who initiated tramadol or diclofenac (positive comparator); and (3) patients who initiated tramadol or codeine (a commonly used weak opioid). The outcome was incident MI over six-months. RESULTS: Among tramadol and naproxen initiators (n = 33,024 in each cohort), 77 (4.8/1000 person-years) and 46 (2.8/1000 person-years) incident MI occurred, respectively. The rate difference (RD) and hazard ratios (HR) for incident MI with tramadol initiation were 1.9 (95% confidence interval [CI] 0.6 to 2.3)/1000 person-years and 1.68 (95% CI 1.16 to 2.41) relative to naproxen initiation, respectively. Among tramadol and diclofenac initiators (n = 18,662 in each cohort), 58 (6.4/1000 person-years) and 47 (5.1/1000 person-years) incident MIs occurred, respectively. The corresponding RD and HR for incident MI were 1.2 (95%CI -2.1 to 14.1)/1000 person-years and 1.24 (95%CI 0.84 to 1.82), respectively. Among tramadol and codeine initiators (n = 42,722 in each cohort), 127 (6.1/1000 person-years) and 103 (5.0/1000 person-years) incident MI occurred, respectively, and the corresponding RD and HR were 1.1 (95%CI:-0.3 to 2.5)/1000 person-years and 1.23 (95%CI:0.95 to 1.60), respectively. CONCLUSIONS: In this population-based cohort of patients with OA, the six-month risk of MI among initiators of tramadol was higher than that of naproxen, but comparable to, if not lower than, those of diclofenac or codeine.

Continued Prescribing of Periprocedural Codeine and Tramadol to Children after a Black Box Warning.

BACKGROUND: Codeine and tramadol are commonly used analgesics in surgery. In 2013, the Food and Drug Administration (FDA) issued a contraindication to the use of codeine in tonsillectomy and adenoidectomy patients aged below 18 y. This warning was expanded in April 2017 to include tramadol and all children aged below 12 y. We sought to describe the prescribing of codeine and tramadol to contraindicated populations in Wisconsin before and after the release of the expanded FDA warning. MATERIALS AND METHODS: Using a statewide Wisconsin claims database, we identified common pediatric ambulatory surgical procedures across the specialties of otolaryngology, urology, general surgery, orthopedics, and ophthalmology. For these procedures, we examined the rates of perioperative codeine and tramadol prescription fills and change in prescribing after the FDA contraindication. RESULTS: Surgeons in all of the specialties studied continued to prescribe codeine to pediatric patients after the contraindication, but tramadol was rarely prescribed. Procedures with relatively high rates of codeine fills were strabismus repair (65% of opioid fills), circumcision >1 yo (22%), and laparoscopic appendectomy (15%). Codeine fills significantly declined after the contraindication to 6% for circumcision >1 yo and 5% for orchiopexy and inguinal hernia repair. Otolaryngology, which was subject to the 2013 codeine contraindication, has low rates of codeine fills (under 2.5%) for the whole period studied. Codeine prescribing for strabismus repair showed no significant decline. CONCLUSIONS: Codeine, and to a lesser extent tramadol, continue to be prescribed to contraindicated populations of children. This represents a target for future de-implementation interventions.

Dihydrocodeine for detoxification and maintenance treatment in individuals with opiate use disorders.

BACKGROUND: Medical treatment and detoxification from opiate disorders includes oral administration of opioid agonists. Dihydrocodeine (DHC) substitution treatment is typically low threshold and therefore has the capacity to reach wider groups of opiate users. Decisions to prescribe DHC to patients with less severe opiate disorders centre on its perceived safety, reduced toxicity, shorter half-life and more rapid onset of action, and potential retention of patients. This review set out to investigate the effects of DHC in comparison to other pharmaceutical opioids and placebos in the detoxification and substitution of individuals with opiate use disorders. OBJECTIVES: To investigate the effectiveness of DHC in reducing illicit opiate use and other health-related outcomes among adults compared to other drugs or placebos used for detoxification or substitution therapy. SEARCH METHODS: In February 2019 we searched Cochrane Drugs and Alcohol's Specialised Register, CENTRAL, PubMed, Embase and Web of Science. We also searched for ongoing and unpublished studies via ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and Trialsjournal.com. All searches included non-English language literature. We handsearched references of topic-related systematic reviews and the included studies. SELECTION CRITERIA: We included randomised controlled trials that evaluated the effect of DHC for detoxification and maintenance substitution therapy for adolescent (aged 15 years and older) and adult illicit opiate users. The primary outcomes were abstinence from illicit opiate use following detoxification or maintenance therapy measured by self-report or urinalysis. The secondary outcomes were treatment retention and other health and behaviour outcomes. DATA COLLECTION AND ANALYSIS: We followed the standard methodological procedures that are outlined by Cochrane. This includes the GRADE approach to appraise the quality of evidence. MAIN RESULTS: We included three trials (in five articles) with 385 opiate-using participants that measured outcomes at different follow-up periods in this review. Two studies with 150 individuals compared DHC with buprenorphine for detoxification, and one study with 235 participants compared DHC to methadone for maintenance substitution therapy. We downgraded the quality of evidence mainly due to risk of bias and imprecision. For the two studies that compared DHC to buprenorphine, we found low-quality evidence of no significant difference between DHC and buprenorphine for detoxification at six-month follow-up (risk ratio (RR) 0.59, 95% confidence interval (CI) 0.25 to 1.39; P = 0.23) in the meta-analysis for the primary outcome of abstinence from illicit opiates. Similarly, low-quality evidence indicated no difference for treatment retention (RR 1.29, 95% CI 0.99 to 1.68; P = 0.06). In the single trial that compared DHC to methadone for maintenance substitution therapy, the evidence was also of low quality, and there may be no difference in effects between DHC and methadone for reported abstinence from illicit opiates (mean difference (MD) -0.01, 95% CI -0.31 to 0.29). For treatment retention at six months' follow-up in this single trial, the RR calculated with an intention-to-treat analysis also indicated that there may be no difference between DHC and methadone (RR 1.04, 95% CI 0.94 to 1.16). The studies that compared DHC to buprenorphine reported no serious adverse events, while the DHC versus methadone study reported one death due to methadone overdose. AUTHORS' CONCLUSIONS: We found low-quality evidence that DHC may be no more effective than other commonly used pharmacological interventions in reducing illicit opiate use. It is therefore premature to make any conclusive statements about the effectiveness of DHC, and it is suggested that further high-quality studies are conducted, especially in low- to middle-income countries.

Oral Opioid Use during Vaginal Delivery Hospitalizations.

OBJECTIVE: This study aimed to determine the receipt of short-acting opioid medications during vaginal delivery hospitalizations. STUDY DESIGN: The Perspective database was analyzed to evaluate patterns of short-acting oral opioid use during vaginal delivery hospitalizations from January 2006 to March 2015. Unadjusted and adjusted models evaluating the role of demographic and hospital factors were created evaluating use of opioids. Hospital-level rates of opioid use were evaluated. Opioid receipt among women with opioid abuse or dependence was evaluated based on overall hospital rates of opioid use. RESULTS: Of 3,785,396 vaginal delivery hospitalizations from 2006 to 2015, 1,720,899 (45.5%) women received an oral opioid for pain relief. Opioid use varied significantly among the 458 hospitals included in the analysis, with one-third of hospitals providing opioids to <38% of patients, one-third to 38 to <59% of patients, and one-third to ≥59% of patients. When hospitals were stratified by overall opioid administration rates, women with opioid abuse or dependence were less likely to be given opioids in hospitals with low overall opioid rates. DISCUSSION: The use of opioid pain medications during vaginal delivery hospitalizations varied significantly among hospitals, suggesting that standardization of pain management practices could reduce opioid use.

Comparisons of In Vivo and In Vitro Opioid Effects of Newly Synthesized 14-Methoxycodeine-6-O-sulfate and Codeine-6-O-sulfate.

The present work represents the in vitro (potency, affinity, efficacy) and in vivo (antinociception, constipation) opioid pharmacology of the novel compound 14-methoxycodeine-6-O-sulfate (14-OMeC6SU), compared to the reference compounds codeine-6-O-sulfate (C6SU), codeine and morphine. Based on in vitro tests (mouse and rat vas deferens, receptor binding and [35S]GTPγS activation assays), 14-OMeC6SU has µ-opioid receptor-mediated activity, displaying higher affinity, potency and efficacy than the parent compounds. In rats, 14-OMeC6SU showed stronger antinociceptive effect in the tail-flick assay than codeine and was equipotent to morphine, whereas C6SU was less efficacious after subcutaneous (s.c.) administration. Following intracerebroventricular injection, 14-OMeC6SU was more potent than morphine. In the Complete Freund's Adjuvant-induced inflammatory hyperalgesia, 14-OMeC6SU and C6SU in s.c. doses up to 6.1 and 13.2 µmol/kg, respectively, showed peripheral antihyperalgesic effect, because co-administered naloxone methiodide, a peripherally acting opioid receptor antagonist antagonized the measured antihyperalgesia. In addition, s.c. C6SU showed less pronounced inhibitory effect on the gastrointestinal transit than 14-OMeC6SU, codeine and morphine. This study provides first evidence that 14-OMeC6SU is more effective than codeine or C6SU in vitro and in vivo. Furthermore, despite C6SU peripheral antihyperalgesic effects with less gastrointestinal side effects the superiority of 14-OMeC6SU was obvious throughout the present study.