Positive Toxicology Results Are Not Associated with Emergency Physicians' Opioid Prescribing Behavior.

INTRODUCTION: Given the general lack of literature on opioid and naloxone prescribing guidelines for patients with substance use disorder, we aimed to explore how a physician's behavior and prescribing habits are altered by knowledge of the patient's concomitant use of psychotropic compounds as evident on urine and serum toxicology screens. METHODS: We conducted a retrospective chart review study at a tertiary, academic, Level I trauma center between November 2017-October 2018 that included 358 patients who were discharged from the emergency department (ED) with a diagnosis of fracture, dislocation, or amputation and received an opioid prescription upon discharge. We extracted urine and serum toxicology results, number and amount of prescription opioids upon discharge, and the presence of a naloxone script. RESULTS: The study population was divided into five subgroups that included the following: negative urine and serum toxicology screen; depressants; stimulants; mixed; and no toxicology screens. When comparing the 103 patients in which toxicology screens were obtained to the 255 patients without toxicology screens, we found no statistically significant differences in the total prescribed morphine milligram equivalent (75.0 and 75.0, respectively) or in the number of pills prescribed (15.0 and 13.5, respectively). Notably, none of the 103 patients who had toxicology screens were prescribed naloxone upon discharge. CONCLUSION: Our study found no association between positive urine toxicology results for psychotropically active substances and the rates of opioid prescribing within a single-center, academic ED. Notably, none of the 103 patients who had toxicology screens were prescribed naloxone upon discharge. More research on the associations between illicit drug use, opioids, and naloxone prescriptions is necessary to help establish guidelines for high-risk patients.

Patient-centered Outcomes in Participants of a Buprenorphine Monthly Depot (BUP-XR) Double-blind, Placebo-controlled, Multicenter, Phase 3 Study.

OBJECTIVE: Opioid use disorder (OUD) is associated with physical, social, psychological, and economic burden. This analysis assessed the effects of RBP-6000, referred to as BUP-XR (extended-release buprenorphine), a subcutaneously injected, monthly buprenorphine treatment for OUD compared with placebo on patient-centered outcomes measuring meaningful life changes. METHODS: Patient-centered outcomes were collected in a 24-week, phase 3, placebo-controlled study assessing the efficacy, safety, and tolerability of BUP-XR 300/300 mg (6 × 300 mg) and 300/100 mg (2 × 300 mg followed by 4 × 100 mg) injections in treatment-seeking participants with moderate-to-severe OUD. Measures included the EQ-5D-5L, SF-36v2, Medication Satisfaction Questionnaire, employment/insurance status, and healthcare resource utilization (HCRU). Changes from baseline to end of study were compared across treatment arms, using mixed models for repeated measures. RESULTS: Participants receiving BUP-XR (n = 389) versus placebo (n = 98) had significantly greater changes from baseline on the EQ-5D-5L index (300/300 mg: difference = 0.0636, P = 0.003), EQ-5D-5L visual analog scale (300/300 mg: difference = 5.9, P = 0.017; 300/100 mg: difference = 7.7, P = 0.002), and SF-36v2 physical component summary score (300/300 mg: difference = 3.8, P < 0.001; 300/100 mg: difference = 3.2, P = 0.002). Satisfaction was significantly higher for participants receiving BUP-XR 300/300 mg (88%, P < 0.001) and 300/100 mg (88%, P < 0.001) than placebo (46%). Employment and percentage of insured participants increased by 10.8% and 4.1% with BUP-XR 300/300 mg and 10.0% and 4.7% with 300/100 mg but decreased by 12.6% and 8.4% with placebo. Participants receiving BUP-XR compared with placebo had significantly fewer hospital days per person-year observed. CONCLUSIONS: These results show the feasibility of measuring patient-centered life changes in substance use disorder clinical studies. Participants receiving up to 6 monthly injections of BUP-XR, compared with placebo, reported better health, increased medication satisfaction, increased employment, and decreased healthcare utilization.

Conversion factors for assessment of driving impairment after exposure to multiple benzodiazepines/z-hypnotics or opioids.

AIMS: Norway has introduced legal concentration limits in blood for 28 non-alcohol drugs in driving under the influence cases. As of 2016 this legislation also regulates the assessment of combined effects of multiple benzodiazepines and opioids. We herein describe the employed methodology for the equivalence tables for concentrations of benzodiazepines/z-hypnotics and opioids implemented in the Norwegian Road Traffic Act. METHODS: Legislative limits corresponding to impairment at blood alcohol concentrations (BAC) of 0.02%, 0.05% and 0.12% were established for 15 different benzodiazepines and opioids. This was based on a concept of a linear relationship between blood drug concentration and impairment in drug naïve users. Concentration ratios between these drugs were used to establish conversion factors and calculate net impairment using diazepam and morphine equivalents. RESULTS: Conversion factors were established for 14 benzodiazepines/z-hypnotics (alprazolam, bromazepam, clobazam, clonazepam, etizolam, flunitrazepam, lorazepam, nitrazepam, nordiazepam, oxazepam, phenazepam, temazepam, zolpidem and zopiclone) and two opioids (methadone and oxycodone). CONCLUSIONS: Conversion factors to calculate diazepam and morphine equivalents for benzodiazepines/z-hypnotics and selected opioids, respectively, have been operative in the Norwegian Road Traffic Act as of February 2016. Calculated equivalents can be applied by the courts to meter out sanctions.

Assessment of Alcohol-Induced Dose Dumping with a Hydrocodone Bitartrate Extended-Release Tablet Formulated with CIMA(®) Abuse Deterrence Technology.

BACKGROUND: Greater drug content requirements for extended-release (ER) opioids necessitate greater protection against dose dumping. Hydrocodone ER employs the CIMA(®) Abuse-Deterrence Technology platform, which provides resistance against rapid release of the active moiety when the tablet is manipulated or taken with alcohol. OBJECTIVE: Assess effects of alcohol on hydrocodone ER pharmacokinetics. STUDY DESIGN: Open-label, crossover (January 25-April 30, 2010). SETTING: Single center. PARTICIPANTS: Forty healthy adults. INTERVENTION: Subjects received all four treatments in a randomized manner (separated by a minimum 5-day washout): hydrocodone ER 15 mg with 240 mL water and 240 mL orange juice containing 4, 20, and 40% alcohol in a fasted state. Naltrexone was administered to minimize opioid-related adverse events. MAIN OUTCOME MEASURE: Effect of alcohol on pharmacokinetics of hydrocodone ER assessed by comparing systemic exposure [maximum plasma drug concentration (Cmax) and area under the plasma drug concentration-versus-time curve from time 0 to infinity (AUC0-∞)] after administration with alcohol or with water. RESULTS: Geometric means ratios of hydrocodone ER with 4, 20, and 40% alcohol relative to water were 1.05, 1.09, and 1.14, respectively, for Cmax and 1.07, 1.13, and 1.17, respectively, for AUC0-∞. All 90% confidence intervals for these geometric means ratios fell within the limits of 0.8 and 1.25. Increasing alcohol concentrations did not notably affect systemic exposure but were associated with increased adverse events. CONCLUSIONS: Hydrocodone ER tablets were resistant to dose dumping when administered with alcohol in healthy subjects based on similar systemic exposures observed across all treatments.

Blood testing in chronic pain management.

Blood testing is quickly becoming a useful laboratory tool for opioid prescribers who wish to document and assess patient tolerance, more objectively monitor patient safety, and evaluate patient compliance using information that is not available with traditional urine drug testing (UDT). Blood testing does not need to be performed as frequently as UDT but provides extremely valuable information which can be used to more accurately evaluate patient compliance and assist with interpreting blood toxicology results commonly used in impairment or overdose cases. This narrative review presents the current evidence supporting the use of blood testing within the chronic pain management setting. In addition, this review aims to introduce and discuss the role of routine blood testing within the chronic pain management setting. Blood testing for the purpose of documenting opioid tolerance is a relatively novel tool for pain physicians and as such this review is not intended to be a comprehensive or exhaustive review of the scientific or medical literature. Prescribers must also be aware that this type of laboratory testing need only be administered to chronic pain patients receiving daily opioid therapy. Patients taking infrequent, low dose, or as needed medications are not anticipated to benefit from this type of test. Based on the complexity of both achieving acceptable outcomes with opioid treatment and the legal and societal issues at hand, we feel that the addition of blood concentration levels will become the standard of care in the near future.

Population pharmacokinetic modelling of tramadol using inverse Gaussian function for the assessment of drug absorption from prolonged and immediate release formulations.

This study aimed to develop a population pharmacokinetic model for tramadol that combines different input rates with disposition characteristics. Data used for the analysis were pooled from two phase I bioavailability studies with immediate (IR) and prolonged release (PR) formulations in healthy volunteers. Tramadol plasma concentration-time data were described by an inverse Gaussian function to model the complete input process linked to a two-compartment disposition model with first-order elimination. Although polymorphic CYP2D6 appears to be a major enzyme involved in the metabolism of tramadol, application of a mixture model to test the assumption of two and three subpopulations did not reveal any improvement of the model. The final model estimated parameters with reasonable precision and was able to estimate the interindividual variability of all parameters except for the relative bioavailability of PR vs. IR formulation. Validity of the model was further tested using the nonparametric bootstrap approach. Finally, the model was applied to assess absorption kinetics of tramadol and predict steady-state pharmacokinetics following administration of both types of formulations. For both formulations, the final model yielded a stable estimate of the absorption time profiles. Steady-state simulation supports switching of patients from IR to PR formulation.

Interpretation of oxycodone concentrations in oral fluid.

OBJECTIVE: The purpose of this retrospective study was to compare oxycodone concentrations in saliva and whole blood with a view to propose therapeutic concentrations in oral fluid. Oral fluid is an easy specimen to collect with several advantages over urine, including ease of collection and difficulty of adulteration. As oral fluid is a reflection of free drug circulating in the blood, drug concentrations in saliva are more closely related to blood levels than urine concentrations. The number of testing laboratories offering the analysis of prescription pain medications in urine has increased significantly over the last few years, along with the overuse and abuse of pain killing drugs, specifically oxycodone. Hence, the utility of oral fluid analysis in this field was assessed. DESIGN: Paired specimens of blood and oral fluid were retrospectively studied in an attempt to establish a range for oxycodone concentrations in oral fluid reflective of therapeutic intake. Twenty-three paired oral fluid-blood specimens were studied. Oral fluid samples had been collected with the Quantisal™ oral fluid device, stored cold and shipped overnight to the laboratory prior to testing. Blood specimens were collected simultaneously in gray top tubes. RESULTS: From 23 pairs of samples, the median concentration in oral fluid was 524 µg/L and blood was 53 µg/L. The whole blood to plasma ratio for oxycodone was 1.3, so the median plasma concentration was 41 µg/L projecting a saliva to plasma ratio (S:P ratio) of 12. The comparison of oral fluid-blood concentrations allowed the projection of a S:P ratio for oxycodone and the development of a potential therapeutic range for oxycodone in oral fluid. CONCLUSION: Saliva drug concentrations in pain management are more closely related to blood levels than urine so can be more easily interpreted. These data provide a foundation for interpretative advances; however, further research surrounding other pain medications and controlled studies are necessary.

What is the case for prescribing long-acting opioids over short-acting opioids for patients with chronic pain? A critical review.

INTRODUCTION: Effective pain management requires appropriate patient assessment, ongoing reassessment, and an understanding of the options available for the treatment of patients with chronic pain. Opioids have long been an important option in the management of moderate to severe chronic pain, but optimal use requires understanding the variety of choices currently available. METHODS: Literature search was carried out using PubMed. Search terms included "steady state," "pharmacokinetics," "pharmacodynamics," "chronic non-cancer pain," "sustained release opioid," "extended release opioid," "controlled release opioid," "morphine," "oxymorphone," "hydromorphone," "oxycodone," and "fentanyl." RESULTS: This search found 12 chronic pain studies that compared short- and long-acting opioids head-to-head. These were supplemented with representative studies from the chronic pain literature. DISCUSSION: The objective of this article is to review clinical data for the use of long-acting and short-acting opioids in a variety of chronic noncancer pain conditions. Although some patients with chronic pain appear to prefer short-acting opioids, many patients receiving long-acting opioid formulations show improved treatment responses and better perception of quality of life. In addition, the sustained reductions in pain seen with long-acting opioid formulations may promote patients' focus on daily activities rather than on their pain, thereby improving therapy adherence and reducing pain-related anxieties. CONCLUSION: Long-term clinical trials of these formulations are needed to allow clinicians to make informed decisions about which patient groups might benefit most from these formulations.

No evidence for the development of acute tolerance to analgesic, respiratory depressant and sedative opioid effects in humans.

It is widely accepted that chronic opioid therapy is associated with the development of pharmacological tolerance. More controversial is the question as to whether acute opioid administration can result in "acute tolerance." The aim of this double-blind, placebo-controlled study in thirty-six healthy human volunteers was to examine whether a 3-h intravenous infusion delivering two different but clinically relevant doses of the mu-opioid receptor agonist remifentanil would result in tolerance to analgesic, respiratory depressant and/or sedative opioid effects. The blood remifentanil concentration versus opioid effect relationship was determined before and after the 3-h infusion. Tolerance was inferred if the potency of remifentanil was significantly lower after the 3-h infusion. Opioid analgesia was assessed with the aid of the cold pressor test and models of electrical and heat pain. Respiratory depression was assessed by measuring arterial pCO2 and minute ventilation. Subjective sedation scores were assessed on a visual analogue scale. Mixed effects modeling was used to relate the steady-state blood remifentanil concentration to each pharmacodynamic assessment. Neither dose of remifentanil produced detectable tolerance to any of the measured opioid effects following a 3-h infusion. The study was adequately powered to detect a decrease in potency of 5-24% for analgesia, 20-48% for respiratory depression, and 32% for sedative effects. These results suggest that short-term administration of clinically useful doses of remifentanil is not associated with the development of significant tolerance to analgesic, respiratory depressant, or sedative opioid effects.

Basic pharmacology relevant to drug abuse assessment: tramadol as example.

Tramadol is a centrally acting analgesic in widespread use throughout the world. Although there is extensive preclinical, clinical, post-marketing and epidemiological data indicating relatively low--but not zero--abuse/dependence, questions continue to arise about its abuse potential and appropriate regulatory classification. This article considers these questions from the point of view of the basic pharmacology of tramadol. There is nothing unique about tramadol in this regard, but its multimodal mechanism of action, pharmacologically active enantiomers, and active metabolite make it a particularly instructive and relevant example.

Efficacy and cost-effectiveness of transdermal fentanyl patches for the relief of post-operative pain in dogs after anterior cruciate ligament and pelvic limb repair.

OBJECTIVES: To determine whether transdermal fentanyl patches provided cost-effective post-operative analgesia in dogs with pelvic limb injuries. STUDY DESIGN: Prospective, randomized, blinded clinical trial. ANIMALS: Twenty-four dogs undergoing repair of ruptured cranial cruciate ligaments or pelvic limb fractures. METHODS: Dogs were randomly assigned to one of two groups: those receiving transdermal fentanyl patches (group F) and those receiving injectable morphine for control of post-operative pain (group M). Patients in both treatment groups were monitored for adequacy of analgesia and alterations in physiological variables. Plasma fentanyl concentrations were measured in Group F. Rescue morphine was given if a dog was deemed uncomfortable. The time of first rescue morphine, the total amount, and number of doses of morphine administered over 72 hours was quantified and compared for each group. RESULTS: There was no significant treatment effect on any of the parameters, except for serum cortisol concentration, which was significantly lower overall in group F (p = 0.01). Pain scores peaked at 6 hours post-extubation and were higher than baseline from 2 to 20 hours post-extubation. Cortisol concentrations were the highest at time 0 (extubation) and were significantly higher than baseline until 2 hours post-extubation. Pain scores correlated with fentanyl plasma concentrations (p = 0.0001 and p = 0.01, respectively), but the correlation was low (r = 0.26 and r = 0.16, respectively). No correlation was found between serum cortisol concentrations and pain scores in either group. Fentanyl cost and total cost for pain management were considerably higher for group F. CONCLUSIONS: Fentanyl patches did not provide better analgesia or a reduced requirement for rescue opioid compared with intramuscular morphine. CLINICAL RELEVANCE: When considering overall costs to the client for comparable analgesic intervention, fentanyl patches increased rather than decreased cost during the first 24 hours post-operatively.

Pharmacokinetic model and simulations of dose conversion from immediate- to extended-release tramadol.

OBJECTIVE: Extended-release tramadol (tramadol ER) is a once-daily formulation of tramadol approved in the United States for moderate to moderately severe chronic pain in adults. This modeling and simulation analysis was conducted to support dosing recommendations for switching patients receiving immediate-release tramadol (tramadol IR) to tramadol ER. RESEARCH DESIGN AND METHODS: Monte Carlo simulations based on steady-state data from three Phase 1 studies predicted minimum plasma concentration (C(min)), maximum plasma concentration (C(max)), and area under the plasma-concentration-versus-time curve (AUC). MAIN OUTCOME MEASURES: Pharmacokinetic parameters were compared between 100-mg daily increments of tramadol ER every 24 h (Q24H) and corresponding 25-mg increments of tramadol IR every 6 h (Q6H), such as tramadol ER 200 mg Q24H versus tramadol IR 200, 225, 250, and 275 mg daily. RESULTS: Tramadol ER and IR were predicted to provide similar exposure (AUC) at a total daily dose of 100, 200, or 300 mg. Estimated exposure was comparable between tramadol IR 125-, 225-, and 325-mg and tramadol ER 100-, 200-, and 300-mg, respectively. Estimated exposure was 30-41% lower with tramadol ER 100 mg versus tramadol IR 150 and 175 mg daily, 15-26% lower with tramadol ER 200 mg versus tramadol IR 250 and 275 mg daily, and 8-19% lower with tramadol ER 300 mg versus tramadol IR 350 and 375 mg daily. CONCLUSIONS: This pharmacokinetic analysis supports switching patients from a total daily dose of tramadol IR 200 or 300 mg directly to tramadol ER 200 and 300 mg once daily, respectively. Patients who take other doses of tramadol IR may switch to the next lower 100-mg increment of tramadol ER (e.g., from tramadol IR 225, 250, or 275 mg daily in divided doses to tramadol ER 200 mg once daily). Confirmation of these findings would require clinical studies comparing the systemic exposure of tramadol upon switching from the IR to the ER formulation.

Assessment of serum concentrations and sedative effects of fentanyl after transdermal administration at three dosages in healthy llamas.

OBJECTIVE: To determine the serum concentrations and sedative effects of fentanyl after transdermal administration at 3 dosages in llamas. ANIMALS: 9 healthy adult female llamas (mean age, 8 +/- 3 years; mean weight, 150 +/- 18 kg). PROCEDURE: Llamas were allocated to 1 of 3 groups (3 llamas/group). Fentanyl patches (each providing transdermal delivery of 75 microg of fentanyl/h) were placed on shaved areas of the antebrachium of all llamas. In group 1, llamas were treated with 1 patch (anticipated fentanyl dosage, 75 microg/h). In group 2, llamas were treated with 2 patches (anticipated fentanyl dosage, 150 microg/h). In group 3, llamas were treated with 4 patches (anticipated fentanyl dosage, 300 microg/h). For each llama, the degree of sedation was assessed by use of a subjective scoring system and a blood sample was collected for determination of serum fentanyl concentration at 12, 24, 36, 48, 60, and 72 hours after patch placement. RESULTS: Following the placement of 4 patches, mean +/- SD serum fentanyl concentration in group 3 llamas reached 0.3 +/- 0.08 ng/mL within 12 hours. This concentration was sustained for 72 hours. In group 2, application of 2 patches provided inconsistent results; in group 1, application of 1 patch rarely provided measurable serum fentanyl concentrations. No llamas became sedated at any time. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that application of four 75 microg/h fentanyl patches provides consistent, sustained serum fentanyl concentrations without sedation in llamas. However, the serum concentration of fentanyl that provides analgesia in llamas is not known.

Assessment of complex peptide degradation pathways via structured multicompartmental modeling approaches: the metabolism of dynorphin A1-13 and related fragments in human plasma.

Peptide metabolic pathways in blood or other tissues are often complex because multiple enzyme systems are involved in the degradation of parent drug and its metabolites. Michaelis-Menten-type studies with isolated enzymes have been frequently employed for evaluating the metabolism of peptides. Alternatively, studies with selective enzyme inhibitors or the evaluation of the area under the drug- or metabolite-time profiles have been employed. We tested in this study the usefulness of a multicompartmental pharmacokinetic approach for the assessment of the apparent first-order metabolism of dynorphin A1-13 up to the fourth metabolite generation in human plasma. This multicompartmental kinetic analysis proved instrumental in clarifying ambiguous degradation pathways not easily detectable by the other methods of assessment (enzyme inhibition studies and noncompartmental analysis) because of the lack of specific enzyme inhibitors or specificity problems of the analytical technique employed. The proposed multicompartmental fitting approach was also highly suitable to verify the overall metabolic pathways suggested by the other methods up to the fourth metabolite by testing whether the rate constants obtained by these methods are suitable to describe the overall degradation profile after Dyn A1-13 degradation. Local sensitivity analysis for the degradation of DYNA 1-13 revealed that the model was, however, not able to adequately identify on its own all of the parameters involved in the degradation of dynorphin A1-13. Thus, the method proved beneficial in evaluating and testing the correctness of the overall degradation pathways suggested by other methods.

A study of the use of a transdermal fentanyl patch in cats.

A transdermal therapeutic system (TTS) has been developed for the continuous delivery of fentanyl citrate to provide ongoing analgesia in human patients with chronic pain. Several researchers believe that fentanyl transdermal patches have a place in postoperative pain control. The purpose of this study was to determine whether transdermal technology is an effective way of administering fentanyl to feline patients. Fentanyl patches were applied to the skin of six cats, and blood samples for fentanyl analysis were collected over 104 hours. This study establishes that the transdermal patch technology is an effective, long-lasting, cost-effective, noninvasive, and well-tolerated mode of deliverying fentanyl to cats.