The Role of Pharmacogenomics in Opioid Prescribing.

OPINION STATEMENT: Pharmacogenomics is increasingly important to guide objective, safe, and effective individualised prescribing. Personalised prescribing has revolutionised treatments in the past decade, allowing clinicians to maximise drug efficacy and minimise adverse effects based on a person's genetic profile. Opioids, the gold standard for cancer pain relief, are among the commonest medications prescribed in palliative care practice. This narrative review examines the literature surrounding opioid pharmacogenomics and its applicability to the palliative care cancer population. There is currently limited intersection between the fields of palliative care and pharmacogenomics, but growing evidence presents a need to build linkages between the two disciplines. Pharmacogenomic evidence guiding opioid prescribing is currently available for codeine and tramadol, which relates to CYP2D6 gene variants. However, these medications are prescribed less commonly for pain in palliative care. Research is accelerating with other opioids, where oxycodone (CYP2D6) and methadone (CYP2B6, ABCB1) already have moderate evidence of an association in terms of drug metabolism and downstream analgesic response and side effects. OPRM1 and COMT are receiving increasing attention and have implications for all opioids, with changes in opioid dosage requirements observed but they have not yet been studied widely enough to be considered clinically actionable. Current evidence indicates that incorporation of pharmacogenomic testing into opioid prescribing practice should focus on the CYP2D6 gene and its actionable variants. Although opioid pharmacogenomic tests are not widely used in clinical practice, the progressively reducing costs and rapid turnover means greater accessibility and affordability to patients, and thus, clinicians will be increasingly asked to provide guidance in this area. The upsurge in pharmacogenomic research will likely discover more actionable gene variants to expand international guidelines to impact opioid prescribing. This rapidly expanding area requires consideration and monitoring by clinicians in order for key findings with clinical implications to be accessible, meaningfully interpretable and communicated.

Implementing a pragmatic clinical trial to tailor opioids for acute pain on behalf of the IGNITE ADOPT PGx investigators.

Opioid prescribing for postoperative pain management is challenging because of inter-patient variability in opioid response and concern about opioid addiction. Tramadol, hydrocodone, and codeine depend on the cytochrome P450 2D6 (CYP2D6) enzyme for formation of highly potent metabolites. Individuals with reduced or absent CYP2D6 activity (i.e., intermediate metabolizers [IMs] or poor metabolizers [PMs], respectively) have lower concentrations of potent opioid metabolites and potentially inadequate pain control. The primary objective of this prospective, multicenter, randomized pragmatic trial is to determine the effect of postoperative CYP2D6-guided opioid prescribing on pain control and opioid usage. Up to 2020 participants, age ≥8 years, scheduled to undergo a surgical procedure will be enrolled and randomized to immediate pharmacogenetic testing with clinical decision support (CDS) for CYP2D6 phenotype-guided postoperative pain management (intervention arm) or delayed testing without CDS (control arm). CDS is provided through medical record alerts and/or a pharmacist consult note. For IMs and PM in the intervention arm, CDS includes recommendations to avoid hydrocodone, tramadol, and codeine. Patient-reported pain-related outcomes are collected 10 days and 1, 3, and 6 months after surgery. The primary outcome, a composite of pain intensity and opioid usage at 10 days postsurgery, will be compared in the subgroup of IMs and PMs in the intervention (n = 152) versus the control (n = 152) arm. Secondary end points include prescription pain medication misuse scores and opioid persistence at 6 months. This trial will provide data on the clinical utility of CYP2D6 phenotype-guided opioid selection for improving postoperative pain control and reducing opioid-related risks.

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.

Managing postoperative pain in adult outpatients: a systematic review and meta-analysis comparing codeine with NSAIDs.

BACKGROUND: Analgesics that contain codeine are commonly prescribed for postoperative pain, but it is unclear how they compare with nonopioid alternatives. We sought to compare the effectiveness of codeine and nonsteroidal anti-inflammatory drugs (NSAIDs) for adults who underwent outpatient surgery. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials comparing codeine and NSAIDs for postoperative pain in outpatient surgery. We searched MEDLINE and Embase from inception to October 2019 for eligible studies. Our primary outcome was the patient pain score, converted to a standard 10-point intensity scale. Our secondary outcomes were patient-reported global assessments and adverse effects. We used random-effects models and grading of recommendations assessment, development and evaluation (GRADE) to assess the quality of evidence. RESULTS: Forty studies, including 102 trial arms and 5116 patients, met inclusion criteria. The studies had low risk of bias and low-to-moderate heterogeneity. Compared with codeine, NSAIDs were associated with better pain scores at 6 hours (weighted mean difference [WMD] 0.93 points, 95% confidence interval [CI] 0.71 to 1.15) and at 12 hours (WMD 0.79, 95% CI 0.38 to 1.19). Stronger NSAID superiority at 6 hours was observed among trials where acetaminophen was coadministered at equivalent doses between groups (WMD 1.18, 95% CI 0.87 to 1.48). NSAIDs were associated with better global assessments at 6 hours (WMD -0.88, 95% CI -1.04 to -0.72) and at 24 hours (WMD -0.67, 95% CI -0.95 to -0.40), and were associated with fewer adverse effects, including bleeding events. INTERPRETATION: We found that adult outpatients report better pain scores, better global assessments and fewer adverse effects when their postoperative pain is treated with NSAIDs than with codeine. Clinicians across all specialties can use this information to improve both pain management and opioid stewardship.

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.

Patient-Centered Decision-making for Postoperative Narcotic-Free Endocrine Surgery: A Randomized Clinical Trial.

Importance: Historically, opioid pain medications have been overprescribed following thyroid and parathyroid surgery. Many narcotic prescriptions are incompletely consumed, creating waste and opportunities for abuse. Objective: To determine whether limiting opioid prescriptions after outpatient thyroid and parathyroid surgery to patients who opt in to narcotic treatment reduces opioid consumption without increasing postoperative pain compared with usual care (routine narcotic prescriptions). Design, Setting, and Participants: A randomized clinical trial of Postoperative Opt-In Narcotic Treatment (POINT) or routine narcotic prescription (control) was conducted at a single tertiary referral center from June 1 to December 30, 2020. A total of 180 adults undergoing ambulatory cervical endocrine surgery, excluding patients currently receiving opioids, were assessed for eligibility. POINT patients received perioperative pain management counseling and were prescribed opioids only on patient request. Patients reported pain scores (0-10) and medication use through 7 daily postoperative surveys. Logistic regression was used to determine factors associated with opioid consumption. Interventions: Patients in the POINT group were able to opt in or out of receiving prescriptions for opioid pain medication on discharge. Control patients received routine opioid prescriptions on discharge. Main Outcomes and Measures: Daily peak pain score through postoperative day 7 was the primary outcome. Noninferiority was defined as a difference less than 2 on an 11-point numeric rating scale from 0 to 10. Analysis was conducted on the evaluable population. Results: Of the 180 patients assessed for eligibility, the final study cohort comprised 102 patients: 48 randomized to POINT and 54 to control. Of these, 79 patients (77.5%) were women and median age was 52 (interquartile range, 43-62) years. A total of 550 opioid tablets were prescribed to the control group, and 230 tablets were prescribed to the POINT group, in which 23 patients (47.9%) opted in for an opioid prescription. None who opted out subsequently required rescue opioids. In the first postoperative week, 17 POINT patients (35.4% of survey responders in the POINT group) reported consuming opioids compared with 27 (50.0%) control patients (P = .16). Median peak outpatient pain scores were 6 (interquartile range, 4-8) in the control group vs 6 (interquartile range, 5-7) in the POINT group (P = .71). In multivariate analysis, patients with a history of narcotic use were 7.5 times more likely to opt in (95% CI, 1.61-50.11; P = .02) and 4.8 times more likely to consume opioids (95% CI, 1.04-1.52; P = .01). Higher body mass index (odds ratio, 1.11; 95% CI, 1.01-1.23; P = .03) and highest inpatient postoperative pain score (odds ratio, 1.24; 95% CI, 1.04-1.52; P = .02) were also associated with opioid consumption. Conclusions and Relevance: In this trial, an opt-in strategy for postoperative narcotics reduced opioid prescription without increasing pain after cervical endocrine surgery. Trial Registration: ClinicalTrials.gov Identifier: NCT04710069.

The effect of codeine administration on oxidative stress biomarkers and the expression of the neuron-specific enolase in the brain of Wistar rats.

The study aimed to assess the effects of codeine medication on some oxidative stress parameters and how it affects the expression of enolase in neuronal cells. The codeine medication used for the study was Archilin™ with codeine syrup and dihydrocodeine 30 mg. The study used 30 male Wistar rats which were grouped in five: A, B, C, D, and E (n = 6), while treatments were administered for 21 days. Based on the LD50s of 6.09 ml/kg body weight (b.wt.) Archilin™ with codeine syrup and 3.145 mg/kg b.wt. dihydrocodeine, group A served as control and were given normal saline; groups B and C were treated with 1 mg/kg and 2 mg/kg b.wt. dihydrocodeine, respectively; while groups D and E were treated with 2 ml/kg and 4 ml/kg b.wt. Archilin™ with codeine syrup, respectively. After treatments, animals were sacrificed via cervical dislocation and the brains were harvested and prepared for determination of oxidative stress biomarkers as well as immunohistochemical studies of neuron-specific enolase (NSE) to assess for neuronal cell integrity. Significantly decreased mean values (p < 0.05) of superoxide dismutase (SOD) and catalase (CAT) activities were observed while malondialdehyde (MDA) is significantly increased (p < 0.05) among treated groups. The expression of enolase was downregulated in treatment groups when compared to control. Animals in group A which are control showed strong staining intensity of the prefrontal cortex compared to groups C, D, and E which showed mild staining. The scoring of group A for cerebellum showed strong staining intensity, groups B and C showed mild staining, while groups D and E showed weak staining intensity. From the findings of this study, prolonged codeine syrup administration causes oxidative stress and this affects the expression of enolase in neuronal cells resulting in glucose hypometabolism which eventually results in functional brain failure.

Relationship of perioperative anaphylaxis to neuromuscular blocking agents, obesity, and pholcodine consumption: a case-control study.

BACKGROUND: The observation that patients presenting for bariatric surgery had a high incidence of neuromuscular blocking agent (NMBA) anaphylaxis prompted this restricted case-control study to test the hypothesis that obesity is a risk factor for NMBA anaphylaxis, independent of differences in pholcodine consumption. METHODS: We compared 145 patients diagnosed with intraoperative NMBA anaphylaxis in Western Australia between 2012 and 2020 with 61 patients with cefazolin anaphylaxis with respect to BMI grade, history of pholcodine consumption, sex, age, comorbid disease, and NMBA type and dose. Confounding was assessed by stratification and binomial logistic regression. RESULTS: Obesity (odds ratio [OR]=2.96, χ2=11.7, P=0.001), 'definite' pholcodine consumption (OR=14.0, χ2=2.6, P<0.001), and female sex (OR=2.70, χ2=9.61, P=0.002) were statistically significant risk factors for NMBA anaphylaxis on univariate analysis. The risk of NMBA anaphylaxis increased with BMI grade. Confounding analysis indicated that both obesity and pholcodine consumption remained important risk factors after correction for confounding, but that sex did not. The relative rate of rocuronium anaphylaxis was estimated to be 3.0 times that of vecuronium using controls as an estimate of market share, and the risk of NMBA anaphylaxis in patients presenting for bariatric surgery was 8.8 times the expected rate (74.9 vs 8.5 per 100 000 anaesthetic procedures). CONCLUSIONS: Obesity is a risk factor for NMBA anaphylaxis, the risk increasing with BMI grade. Pholcodine consumption is also a risk factor, and this is consistent with the pholcodine hypothesis. Rocuronium use is associated with an increased risk of anaphylaxis compared with vecuronium in this population.

Testicular toxicity following chronic codeine administration is via oxidative DNA damage and up-regulation of NO/TNF-α and caspase 3 activities.

BACKGROUND: Codeine, a 3-methylmorphine, and other related opioids have been implicated in androgen suppression, although the associated mechanisms remain unclear. AIM: Therefore, the objective of the current study was to elucidate the in vivo molecular mechanisms underlying codeine-induced androgen suppression. METHODS: This study made use of twenty-one healthy male rabbits, distributed into three groups randomly, control and codeine-treated groups. The control had 1ml of normal saline daily p.o. The codeine-treated groups received either 4mg/kg b.w of codeine or 10mg/kg b.w of codeine p.o. for six weeks. Reproductive hormonal profile, testicular weight, testicular enzymes, oxidative and inflammatory parameters, testicular DNA fragmentation, histological examination and apoptosis marker were evaluated to examine the effects of codeine use. KEY FINDINGS: Oral administration of codeine resulted in testicular atrophy and alterations in testicular histomorphology, elevated testicular enzymes, and suppression of circulatory and intra-testicular testosterone. These changes were associated with a marked rise in oxidative markers and decline in the activities of testicular enzymatic antioxidants, as well as oxidative DNA damage, inflammatory response, testicular DNA fragmentation, and caspase-dependent apoptosis (p<0.05). SIGNIFICANCE: In conclusion, chronic codeine use resulted in testicular degeneration and testosterone suppression, which is attributable to TNF-α/nitric oxide-/oxidative stress-mediated caspase-dependent apoptotic testicular cell death and loss of testicular function.

A study of the use of post-operative opioid analgesics following rhinology surgery in 35 patients.

OBJECTIVE: Opioid analgesics are often prescribed following rhinology surgery. This study aimed to evaluate whether the quantity of opioid analgesics prescribed is justified. METHODS: Patients were asked about their pain management post-operatively. Parameters recorded included: current pain (using a 10-point Likert scale); type of operation; the opioid analgesics prescribed; and the quantity of opioid tablets taken and other methods of pain relief used. RESULTS: Thirty-five patients were successfully contacted. The median pain score at one week post-operation was 1 (interquartile range, 0-3). Of these 35 patients, 16 were prescribed opioids, whilst 19 were not. Patients prescribed opioids took a median of 8 tablets (interquartile range, 0.8-10.5) out of the 28 tablets prescribed. CONCLUSION: The study shows that the quantity of post-operative opioid analgesics prescribed does not compare with the amount consumed by patients to relieve pain, resulting in a surplus of opioid medication which has the potential to be abused.

Efficacy and Safety of Low-dose Codeine-containing Combination Analgesics for Pain: Systematic Review and Meta-Analysis.

OBJECTIVE: To investigate the efficacy and safety of combination analgesic products containing low-dose codeine (up to 30 mg/dose) for pain. METHODS: Electronic databases were used to identify eligible placebo-controlled, randomized controlled trials (RCTs). Two authors extracted data and assessed the risk of bias. Data were pooled using a random-effects model with the strength of evidence assessed using Grading of Recommendations Assessment, Development and Evaluation. The primary outcome was immediate pain relief (3 hours post administration) on a 0 to 100 pain scale. RESULTS: Ten RCTs were eligible. There is low-quality evidence (4 RCTs, n=211 participants) that a single dose of a combination analgesic product (with an nonsteroidal anti-inflammatory) containing low-dose codeine (15 to 30 mg) provides small pain relief for acute dental pain (mean difference [MD], -12.7; 95% confidence interval [CI], -18.5 to -6.9) and moderate-quality evidence (1 RCT, n=93) of small pain relief for post-episiotomy pain and orthopedic surgery pain (MD,, -10.0; 95% CI, -19.0 to -1.0 and MD, -11.0; 95% CI, -20.7 to -1.3), respectively. There is low-quality evidence (1 RCT, n=80) that a multiple-dose regimen provides small pain relief for acute pain following photorefractive keratectomy (MD, -16.0; 95% CI, -24.5 to -7.5) and moderate-quality evidence of moderate pain relief for certain chronic pain conditions: for hip osteoarthritis (MD, -19.0; 95% CI, -31.2 to -6.8) and for temporomandibular joint pain (MD, -26.0; 95% CI, -44.5 to -7.5). Two studies reported a higher incidence of drowsiness in the treatment group compared with the placebo group (relative risk, 8.50; 95% CI, 1.96, 36.8 and 19.3; 95% CI, 1.2-306.5, respectively). DISCUSSION: There is low to moderate level evidence that combination analgesic products containing low-dose codeine provide small to moderate pain relief for acute and chronic pain conditions in the immediate short term with limited trial data on use beyond 24 hours. Further research examining regular use of these medicines is needed with more emphasis on measuring potential harmful effects.

Pregnancy outcome following opioid exposure: A cohort study.

INTRODUCTION: Opioids constitute a cornerstone of pain relief treatment. However, opioid safety during pregnancy has not been well established. Recent studies reported an association between in utero opioid exposure and spina bifida. METHODS: In order to further evaluate the association of opioids exposure during pregnancy with adverse pregnancy outcomes, we conducted a large historical cohort by linking four databases: medications dispensations, births, pregnancy terminations for medical reasons and infant hospitalizations during the years of 1999-2009. Confounders that were controlled for included maternal age, ethnicity, maternal diabetes, smoking status, parity, obesity, year and folic acid intake. A secondary analysis for total major malformations and for spina bifida was performed using propensity score matching for first trimester exposure. RESULTS: Of the 101,586 women included in the study, 3003 were dispensed opioids during the first trimester. Intrauterine exposure to opioids was not associated with overall major malformations (adjusted odds ratio (aOR) 0.97, 95% CI 0.83-1.13), cardiovascular malformations (aOR = 0.89, 95% CI 0.70-1.13) other malformations by systems or spina bifida in particular. However, the risk for spina bifida among newborns and abortuses who were exposed to codeine was four times higher than that of the unexposed (aOR = 4.42, 95% CI 1.60-12.23). This association remained significant in a secondary analysis using propensity score matching. Third trimester exposure to opioids was not associated with low birth weight (aOR = 1.08, 95% CI 0.77-1.52), perinatal death (aOR = 1.38, 95% CI 0.64-2.99) and other adverse pregnancy outcomes. CONCLUSIONS: These findings suggest that opioids exposure (as a homogenous group) is not a significant risk factor for overall major malformations. Exposure to codeine during the first trimester was found to be associated with increased risk of spina bifida. However, this finding was based on a small number of cases and need to be verified in future work.

A European multicentre drug utilisation study of the impact of regulatory measures on prescribing of codeine for pain in children.

PURPOSE: In June 2013, following recommendations from the World Health Organization (WHO) and Food and Drug Administration (FDA), the European Medicines Agency agreed updates to the codeine product information regarding use for pain in children younger than 12 years and children undergoing tonsillectomy or adenoidectomy (TA) for obstructive sleep apnoea. This study was conducted to (a) assess effectiveness of these measures on codeine prescribing in the "real-world" setting and (b) test feasibility of a study using a common protocol by regulators with access to databases. METHODS: The study was performed using BIFAP (Spain), CPRD (UK), and IMS® Disease Analyzer (France and Germany) databases. Prescribers included general practitioners (GPs) (France and UK), GPs and paediatricians together (Spain), and GPs, paediatricians, and ear, nose, and throat (ENT) specialists separately (Germany). Between January 2010 and June 2015, prevalence of codeine prescribing was obtained every 6 months, and a time series analysis (joinpoint) was performed. Codeine prescribing within ±30 days of TA was also identified. Furthermore, doses, durations, and prior prescribing of other analgesics were investigated. RESULTS: Over the 5-year period, codeine prescribing decreased in children younger than 12 years (by 84% in France and Spain, 44% in GP practices in Germany, and 33% in the United Kingdom). The temporal pattern was compatible with the regulatory intervention in France and the United Kingdom, whereas a decrease throughout the study period was seen in Germany and Spain. Decreased prescribing associated with TA was suggested in ENT practices in Germany. CONCLUSIONS: Codeine prescribing for children decreased in line with introduced regulatory measures. Multidatabase studies assessing impact of measures by EU regulators are feasible.

Comparative Efficacy of Therapeutics for Chronic Cancer Pain: A Bayesian Network Meta-Analysis.

PURPOSE: Opioids are the primary choice for managing chronic cancer pain. However, many nonopioid therapies are currently prescribed for chronic cancer pain with little published evidence comparing their efficacy. METHODS: Electronic databases were searched for randomized controlled trials (RCTs) comparing any systemic pharmaceutical intervention and/or combination thereof in treating chronic cancer pain. The primary outcome was global efficacy reported as an odds ratio (OR). The secondary outcome was change in pain intensity reported as a standardized mean difference (SMD). RESULTS: We included 81 RCTs consisting of 10,003 patients investigating 11 medication classes. Most RCTs (80%) displayed low risk of bias. The top-ranking classes for global efficacy were nonopioid analgesics (network OR, 0.30; 95% credibility interval [CrI], 0.13 to 0.67), nonsteroidal anti-inflammatory drugs (network OR, 0.44; 95% CrI, 0.22 to 0.90), and opioids (network OR, 0.49; 95% CrI, 0.27 to 0.86), whereas the top-ranked interventions were lidocaine (network OR, 0.04; 95% CrI, 0.01 to 0.18; surface under the cumulative ranking curve analysis [SUCRA] score, 98.1), codeine plus aspirin (network OR, 0.22; 95% CrI, 0.08 to 0.63; SUCRA score, 81.1), and pregabalin (network OR, 0.29; 95% CrI, 0.08 to 0.92; SUCRA score, 73.8). In terms of reducing pain intensity, we found that no class was superior to placebo, whereas the following top-ranked interventions were superior to placebo: ziconotide (network SMD, -24.98; 95% CrI, -32.62 to -17.35; SUCRA score, 99.8), dezocine (network SMD, -13.56; 95% CrI, -23.37 to -3.69; SUCRA score, 93.5), and diclofenac (network SMD, -11.22; 95% CrI, -15.91 to -5.80; SUCRA score, 92.9). CONCLUSION: There are significant differences in efficacy among current regimens for chronic cancer pain. Our evidence suggests that certain nonopioid analgesics and nonsteroidal anti-inflammatory drugs can serve as effectively as opioids in managing chronic cancer pain.

Otolaryngology practice patterns in pediatric tonsillectomy: The impact of the codeine boxed warning.

OBJECTIVES/HYPOTHESIS: To determine if otolaryngologists at a single children's hospital were adherent to the boxed warning for codeine use in post-tonsillectomy patients and the implications for practice patterns. STUDY DESIGN: Case series with chart review. METHODS: Charts from all patients undergoing adenotonsillectomy at a single children's hospital from January 1, 2010 through December 31, 2015 were analyzed and stratified according to date (pre- or post-boxed warning) and practitioner type (academic otolaryngologists [AO] vs. nonacademic otolaryngologists [NAO]). Demographic data, surgical technique, method of removal, narcotic prescriptions (dosage and drug), and complications were recorded. Fisher exact test was used to determine the level of significance in prescription rates pre- and postwarning. SPSS version 22 was used for statistical analysis, with P < .05 indicating statistical significance. RESULTS: There were 2,749 children undergoing adenotonsillectomy during the study period, with 1,239 AOs and 1,510 NAOs. There was a distinct downward trend in codeine prescriptions before and after the warning, with the AO group reaching zero sooner than the NAO group. There was a 5% decrease in discharge narcotic prescriptions given postwarning (P < .001), but no significant difference in postoperative emergency department visits or pain-related complications when comparing the two time periods. CONCLUSIONS: Codeine use for management of pediatric post-tonsillectomy pain was essentially zero after issuance of the boxed warning. Total narcotic use decreased significantly without increase in pain- or medication-related complications. Future research should focus on identifying markers of increased susceptibility to adverse medication events and determining the safest options for pain management. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:264-268, 2018.

Comparison of Clinical Efficacies of Preoperatively Initiated Naproxen Sodium-Codeine Phosphate in Combination, Diclofenac Potassium, and Benzydamine Hydrochloride for Pain, Edema, and Trismus After Extraction of Impacted Lower Third Molar: A Randomized Double-Blind Study.

PURPOSE: The aim of this study was to compare the clinical efficacies of naproxen sodium-codeine phosphate in combination, benzydamine hydrochloride, and diclofenac potassium for pain, edema, and trismus after lower third molar extraction. MATERIALS AND METHODS: Ninety healthy volunteers in whom impacted third molar extraction was indicated were randomly distributed into 3 groups. One hour before the tooth-extraction process, patients were administered one of the following drugs: naproxen sodium, 550 mg, and codeine phosphate, 30 mg, in a tablet; diclofenac potassium, 50 mg, in a coated pill; or benzydamine hydrochloride, 50 mg, in a coated pill. Pain assessment was conducted via a visual analog scale; edema assessment, by measuring the distances between predetermined facial landmarks; and trismus assessment, by measuring interincisal distance. Regarding rescue analgesics (paracetamol, 500 mg), the number and time of use by patients were recorded. RESULTS: Naproxen sodium-codeine phosphate was more effective for pain, edema, and trismus than diclofenac potassium and benzydamine hydrochloride (P < .05). Benzydamine hydrochloride yielded similar clinical responses to diclofenac potassium (P > .05). No drug-related side effects were observed. CONCLUSIONS: Naproxen sodium-codeine phosphate constitutes the drug of choice after the extraction of a patient's impacted lower third molar. Benzydamine hydrochloride has similar efficacy to diclofenac potassium, and it can be used as a nonsteroidal anti-inflammatory analgesic drug.

Opioids for cancer pain - an overview of Cochrane reviews.

BACKGROUND: Pain is a common symptom with cancer, and 30% to 50% of all people with cancer will experience moderate to severe pain that can have a major negative impact on their quality of life. Opioid (morphine-like) drugs are commonly used to treat moderate or severe cancer pain, and are recommended for this purpose in the World Health Organization (WHO) pain treatment ladder. The most commonly-used opioid drugs are buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, tramadol, and tapentadol. OBJECTIVES: To provide an overview of the analgesic efficacy of opioids in cancer pain, and to report on adverse events associated with their use. METHODS: We identified systematic reviews examining any opioid for cancer pain published to 4 May 2017 in the Cochrane Database of Systematic Reviews in the Cochrane Library. The primary outcomes were no or mild pain within 14 days of starting treatment, withdrawals due to adverse events, and serious adverse events. MAIN RESULTS: We included nine reviews with 152 included studies and 13,524 participants, but because some studies appeared in more than one review the number of unique studies and participants was smaller than this. Most participants had moderate or severe pain associated with a range of different types of cancer. Studies in the reviews typically compared one type of opioid or formulation with either a different formulation of the same opioid, or a different opioid; few included a placebo control. Typically the reviews titrated dose to effect, a balance between pain relief and adverse events. Various routes of administration of opioids were considered in the reviews; oral with most opioids, but transdermal administration with fentanyl, and buprenorphine. No review included studies of subcutaneous opioid administration. Pain outcomes reported were varied and inconsistent. The average size of included studies varied considerably between reviews: studies of older opioids, such as codeine, morphine, and methadone, had low average study sizes while those involving newer drugs tended to have larger study sizes.Six reviews reported a GRADE assessment (buprenorphine, codeine, hydromorphone, methadone, oxycodone, and tramadol), but not necessarily for all comparisons or outcomes. No comparative analyses were possible because there was no consistent placebo or active control. Cohort outcomes for opioids are therefore reported, as absolute numbers or percentages, or both.Reviews on buprenorphine, codeine with or without paracetamol, hydromorphone, methadone, tramadol with or without paracetamol, tapentadol, and oxycodone did not have information about the primary outcome of mild or no pain at 14 days, although that on oxycodone indicated that average pain scores were within that range. Two reviews, on oral morphine and transdermal fentanyl, reported that 96% of 850 participants achieved that goal.Adverse event withdrawal was reported by five reviews, at rates of between 6% and 19%. Participants with at least one adverse event were reported by three reviews, at rates of between 11% and 77%.Our GRADE assessment of evidence quality was very low for all outcomes, because many studies in the reviews were at high risk of bias from several sources, including small study size. AUTHORS' CONCLUSIONS: The amount and quality of evidence around the use of opioids for treating cancer pain is disappointingly low, although the evidence we have indicates that around 19 out of 20 people with moderate or severe pain who are given opioids and can tolerate them should have that pain reduced to mild or no pain within 14 days. This accords with the clinical experience in treating many people with cancer pain, but overstates to some extent the effectiveness found for the WHO pain ladder. Most people will experience adverse events, and help may be needed to manage the more common undesirable adverse effects such as constipation and nausea. Perhaps between 1 in 10 and 2 in 10 people treated with opioids will find these adverse events intolerable, leading to a change in treatment.

Efficacy of Codeine When Added to Paracetamol (Acetaminophen) and Ibuprofen for Relief of Postoperative Pain After Surgical Removal of Impacted Third Molars: A Double-Blinded Randomized Control Trial.

PURPOSE: The use of opioids in combination with nonopioids is common practice for acute pain management after third molar surgery. One such combination is paracetamol, ibuprofen, and codeine. The authors assessed the efficacy of codeine when added to a regimen of paracetamol and ibuprofen for pain relief after third molar surgery. MATERIALS AND METHODS: This study was a randomized, double-blinded, placebo-controlled trial conducted in patients undergoing the surgical removal of at least 1 impacted mandibular third molar requiring bone removal. Participants were randomly allocated to a control group (paracetamol 1,000 mg and ibuprofen 400 mg) or an intervention group (paracetamol 1,000 mg, ibuprofen 400 mg, and codeine 60 mg). All participants were treated under intravenous sedation and using identical surgical conditions and technique. Postoperative pain was assessed using the visual analog scale (VAS) every 3 hours (while awake) for the first 48 hours after surgery. Pain was globally assessed using a questionnaire on day 3 after surgery. RESULTS: There were 131 participants (36% men; control group, n = 67; intervention group, n = 64). Baseline characteristics were similar for the 2 groups. Data were analyzed using a modified intention-to-treat analysis and, for this, a linear mixed model was used. The model showed that the baseline VAS score was associated with subsequent VAS scores and that, with each 3-hour period, the VAS score increased by an average of 0.08. The treatment effect was not statistically meaningful, indicating there was no difference in recorded pain levels between the 2 groups during the first 48 hours after mandibular third molar surgery. Similarly, the 2 groups did not differ in their global ratings of postoperative pain. CONCLUSION: Codeine 60 mg added to a regimen of paracetamol 1,000 mg and ibuprofen 400 mg does not improve analgesia after third molar surgery.

Impact of Safety-Related Regulations on Codeine Use in Children: A Quasi-Experimental Study Using Taiwan's National Health Insurance Research Database.

INTRODUCTION: Safety concerns regarding potential life-threatening adverse events associated with codeine have resulted in policy decisions to restrict its use in pediatrics. However, whether these drug safety communications have had an immediate and strong impact on codeine use remains in question. OBJECTIVE: We aimed to investigate the impact of the two implemented safety-related regulations (label changes and reimbursement regulations) on the use of codeine for upper respiratory infection (URI) or cough. METHODS: A quasi-experimental study was performed using Taiwan's National Health Insurance Research Database. Quarterly data of codeine prescription rates for URI/cough visits were reported, and an interrupted time series design was used to assess the impact of the safety regulations on the uses of codeine among children with URI/cough visits. Multivariable logistic regression models were used to explore patient and provider characteristics associated with the use of codeine. RESULTS: The safety-related regulations were associated with a significant reduction in codeine prescription rates of -4.24% (95% confidence interval [CI] -4.78 to -3.70), and the relative reduction compared with predicted rates based on preregulation projections was 60.4, 56.6, and 53.2% in the first, second, and third year after the regulations began, respectively. In the postregulation period, physicians specializing in otolaryngology (odds ratio [OR] 1.47, 95% CI 1.45-1.49), practicing in district hospitals (OR 6.84, 95% CI 5.82-8.04) or clinics (OR 6.50, 95% CI 5.54-7.62), and practicing in the least urbanized areas (OR 1.60, 95% CI 1.55-1.64) were more likely to prescribe codeine to children than their counterparts. CONCLUSIONS: Our study provides a successful example of how to effectively reduce the codeine prescriptions in children in the 'real-world' settings, and highlights areas where future effort could be made to improve the safety use of codeine. Future research is warranted to explore whether there was a simultaneous decrease in the incidence rates of codeine-related adverse events following the safety-related regulations.

Efficacy of Preoperative Administration of Paracetamol-Codeine on Pain following Impacted Mandibular Third Molar Surgery: A Randomized, Split-Mouth, Placebo-Controlled, Double-Blind Clinical Trial.

Objectives. The aim of this study was to determine the effectiveness of preoperative administration of single-dose of paracetamol-codeine, in the relieving of acute postoperative pain after the surgical removal of an impacted mandibular third molar. Materials and Methods. The study cohort consisted of 32 Caucasian outpatients, giving a total of 64 bilateral symmetrical impacted mandibles. Patients were randomized in two experimental groups to receive a preoperative oral dose of paracetamol-codeine (analgesic group) or a placebo (placebo group) at the first and second surgeries. Study participants were asked to record pain intensity scores during the operation and the next 2 days, the time of the first request for rescue analgesic, and the total number of postoperative-supplement paracetamol-codeine tablets. Results. The pain intensity score on the first day was significantly lower in the analgesic group than in the placebo group (p < 0.001). The time to using rescue therapy was significantly longer in the analgesic group than in the placebo group (p = 0.004). The number of paracetamol-codeine tablets used postoperatively did not differ between the analgesic and placebo groups (p = 0.104). Conclusions. Preoperative paracetamol-codeine is effective in providing immediate postoperative pain control after third molar surgery and in delaying the initial onset of pain. This trial is registered with ClinicalTrials.gov Identifier (Registration Number): NCT03049878.