Factors Associated with Opioid Dose Increases: A Chart Review of Patients' First Year on Long-Term Opioids.

Objective: To examine encounter-level factors associated with opioid dose increases during patients' first year on opioid therapy for chronic pain. Design: Case-control study analyzing all opioid prescriptions for patients with chronic pain during their first year after opioid initiation. Cases were patients who experienced an overall dose escalation of ≥ 30 mg morphine equivalents over the 1-year period; controls did not experience overall dose escalation. Main measures were encounter type, opioid dose change, documented prescribing rationale, documentation of guideline-concordant opioid-prescribing practices. Two coders reviewed all encounters associated with opioid prescriptions. Analysis of factors associated with dose increases and provider documentation of prescribing rationale was conducted using multiple logistic regression. Results: There were 674 encounters coded for 66 patients (22 cases, 44 controls). Fifty-three percent of opioid prescriptions were associated with telephone encounters; 13% were associated with e-mail encounters. No prescribing rationale was documented for 43% of all opioid prescriptions and 25% of dose increases. Likelihood of dose increase and documentation of prescribing rationale did not significantly differ for cases versus controls. Compared with face-to-face encounters, dose increases were significantly less likely for telephone (OR 0.18, 95% CI 0.11-0.28) and e-mail (OR 0.23, 95% CI 0.12-0.47) encounters; documentation of prescribing rationale was significantly more likely for e-mail (OR 5.06, 95% CI 1.87-13.72) and less likely for telephone (OR 0.30, 95% CI 0.18-0.51) encounters. Conclusion: Most opioid prescriptions were written without face-to-face encounters. One quarter of dose increases contained no documented prescribing rationale. Documented encounter-level factors were not significantly associated with overall opioid dose escalation.

A preliminary evaluation of the relationship of cannabinoid blood concentrations with the analgesic response to vaporized cannabis.

A randomized, placebo-controlled crossover trial utilizing vaporized cannabis containing placebo and 6.7% and 2.9% delta-9-tetrahydrocannabinol (THC) was performed in 42 subjects with central neuropathic pain related to spinal cord injury and disease. Subjects received two administrations of the study medication in a 4-hour interval. Blood samples for pharmacokinetic evaluation were collected, and pain assessment tests were performed immediately after the second administration and 3 hours later. Pharmacokinetic data, although limited, were consistent with literature reports, namely dose-dependent increase in systemic exposure followed by rapid disappearance of THC. Dose-dependent improvement in pain score was evident across all pain scale elements. Using mixed model regression, an evaluation of the relationship between plasma concentrations of selected cannabinoids and percent change in items from the Neuropathic Pain Scale was conducted. Changes in the concentration of THC and its nonpsychotropic metabolite, 11-nor-9-carboxy-THC, were related to percent change from baseline of several descriptors (eg, itching, burning, and deep pain). However, given the large number of multiple comparisons, false-discovery-rate-adjusted P-values were not significant. Plans for future work are outlined to explore the relationship of plasma concentrations with the analgesic response to different cannabinoids. Such an appraisal of descriptors might contribute to the identification of distinct pathophysiologic mechanisms and, ultimately, the development of mechanism-based treatment approaches for neuropathic pain, a condition that remains difficult to treat.

Impact of carprofen administration on stress and nociception responses of calves to cautery dehorning.

The objective of this study was to investigate the effects of carprofen administered immediately before cautery dehorning on nociception and stress. Forty Holstein calves aged approximately 6 to 8 wk old were either placebo treated and sham dehorned ( = 10) or cautery dehorned following administration of carprofen (1.4 mg/kg) subcutaneously ( = 10) or orally ( = 10) or a subcutaneous and oral placebo ( = 10) in a randomized, controlled trial. All animals were given a cornual nerve block using lidocaine before dehorning. Response variables including mechanical nociception threshold, ocular temperature, heart rate, and respiratory rate were measured before and following cautery dehorning for 96 h. Blood samples were also collected over 96 h following dehorning and analyzed for plasma cortisol and substance P concentrations by RIA. Plasma carprofen concentration and ex vivo PGE concentrations were also determined for this time period. Average daily gain was calculated for 7 d after dehorning. Data were analyzed using a linear mixed effects model with repeated measures, controlling for baseline values by their inclusion as a covariate in addition to planned contrasts. Dehorning was associated with decreased nociception thresholds throughout the study and a stress response immediately after dehorning, following the loss of local anesthesia, and 48 h after dehorning compared with sham-dehorned calves. Carprofen was well absorbed after administration and reached concentrations that inhibited ex vivo PGE concentrations for 72 h (subcutaneous) and 96 h (oral) compared with placebo-treated calves ( < 0.05). Carprofen-treated calves tended to be less sensitive ( = 0.097) to nociceptive threshold tests. Overall, at the dosing regimen studied, the effect of carprofen on sensitivity and stress following cautery dehorning was minimal. Consideration of route of administration and dose determination studies may be warranted.

The effects of firocoxib on cautery disbudding pain and stress responses in preweaned dairy calves.

Perioperative analgesic effects of oral firocoxib following cautery disbudding were investigated in preweaned calves. Twenty Holstein calves approximately 4 to 6wk old received a single oral dose of firocoxib, a nonsteroidal antiinflammatory, at 0.5mg/kg (n=10) or placebo (n=10) in a randomized controlled clinical trial. Responses, including ocular temperature determined by infrared thermography, pressure algometry measuring mechanical nociception threshold, and heart rate, were evaluated at 2, 4, 7, 8, and 24h after cornual nerve block and cautery disbudding. Blood samples were collected over 96h and analyzed for plasma cortisol and substance P concentrations by RIA. Additionally, ex vivo prostaglandin E2 concentrations were determined over a 72-h study period using an enzyme immunoassay. Data were analyzed using a linear mixed effects model with repeated measures. An inhibition of ex vivo prostaglandin E2 synthesis was observed from 12 to 48h following disbudding in calves treated with firocoxib. Cautery disbudding was associated with an increased nociception for the duration of sampling (24h). During the initial 24-h period following disbudding, no difference in response between treatment groups was noted. Following 24h, mean cortisol concentrations diverged between the 2 study groups with placebo-treated calves having increased cortisol concentrations at approximately 48h after disbudding. Furthermore, the overall integrated cortisol response as calculated as area under the effect curve tended to be reduced in firocoxib-treated calves. The prolonged effects of cautery dehorning require further investigation. Moreover, the effect of firocoxib on cortisol reduction observed in this study requires additional exploration.

Dose escalation during the first year of long-term opioid therapy for chronic pain.

OBJECTIVE: To identify patient factors and health care utilization patterns associated with dose escalation during the first year of long-term opioid therapy for chronic pain. DESIGN: Retrospective cohort study using electronic health record data. SETTING: University health system. SUBJECTS: Opioid naïve adults with musculoskeletal pain who received a new outpatient opioid prescription between July 1, 2011 and June 30, 2012 and stayed on opioids for 1 year. METHODS: Mixed-effects regression was used to estimate patients' rate of opioid dose escalation. Demographics, clinical characteristics, and health care utilization for patients with and without dose escalation were compared. RESULTS: Twenty-three (9%) of 246 patients in the final cohort experienced dose escalation (defined as an increase in mean daily opioid dose of ≥30-mg morphine equivalents over 1 year). Compared with patients without dose escalation, patients with escalation had higher rates of substance use diagnoses (17% vs 1%, P = 0.01) and more total outpatient encounters (51 vs 35, P = 0.002) over 1 year. Differences in outpatient encounters were largely due to more non face-to-face encounters (e.g., telephone calls, emails) among patients with dose escalation. Differences in age, race, concurrent benzodiazepine use, and mental health diagnoses between patients with and without dose escalation were not statistically significant. Primary care clinicians prescribed 89% of opioid prescriptions. CONCLUSIONS: Dose escalation during the first year of long-term opioid therapy is associated with higher rates of substance use disorders and more frequent outpatient encounters, especially non face-to-face encounters.

Pharmacokinetics of firocoxib in preweaned calves after oral and intravenous administration.

The objective of this study was to determine the pharmacokinetics of intravenous and oral firocoxib in 10 healthy preweaned calves. Firocoxib (0.5 mg/kg) was initially administered i.v. to calves, and following a 14-day washout period, animals received firocoxib orally prior to cautery dehorning. Firocoxib concentrations were determined by liquid chromatography-tandem mass spectrometry. Changes in hematology and plasma chemistry were determined using automated methods. Computer software was used to estimate pharmacokinetic parameters best described with a two-compartment model for i.v. administration and a one-compartment model for p.o. administration. Following i.v. dosing, the geometric mean (range) T1/2K10 and T1/2ß were 6.7 (4.6-9.7) and 37.2 (23.5-160.4) h, respectively, Vss was 3.10 (2.10-7.22) L/kg, and CL was 121.7 (100.1-156.7) mL/h/kg. Following oral administration, geometric mean (range) Cmax was 127.9 (102.5-151.3) ng/mL, Tmax was 4.0 (2.6-5.6) h, and T1/2K10 was 18.8 (14.2-25.5) h. Bioavailability of oral firocoxib was calculated using the AUC derived from both study populations to be 98.4% (83.1-117.6%). No adverse clinical effects were evident following firocoxib administration. Pharmacokinetic analysis of i.v. and p.o. firocoxib indicates high bioavailability and a prolonged terminal half-life in preweaned calves.

Increasing trends in Schedule II opioid use and doctor shopping during 1999-2007 in California.

PURPOSE: To examine the age and gender-specific trends of Schedule II opioid use among California residents, with special reference to multiple provider users (doctor shoppers). METHODS: Utilizing data from the California Prescription Drug Monitoring Program, we examined age and gender-specific trends of Schedule II opioid use during calendar years 1999-2007. Specifically, we analyzed the following: (1) the prevalence of Schedule II opioid users among California's population and (2) the proportion of these opioid users who were doctor shoppers (defined as an individual who used more than five different prescribers for all Schedule II opioids he or she obtained in a calendar year). RESULTS: Among all age and gender groups, the prevalence of Schedule II opioid users in California increased by 150%-280% and the prevalence of doctor shoppers among users increased by 111%-213% over 9 years. The prevalence of opioid users was lowest among 18-44 year old men (1.25%) and highest among 65-year and older women (5.31%) by 2007. The prevalence of doctor shoppers was approximately 1.4% among those up to age 64 years and 0.5% among those 65 years and older. The gender difference in doctor shoppers among all age groups was negligible. On average, the cumulative morphine-equivalent amount of Schedule II opioid per individual obtained per year was threefold to sixfold higher for doctor shoppers than for the general population across different age and gender groups. CONCLUSIONS: Age and gender differences in opioid use were relatively small, whereas the trends for use of opioids and multiple providers grew at a disquieting rate.

Development and refinement of a technique for short-term intravascular auricular vein catheter placement in mature sows.

Intravenous drug administration in adult swine is difficult to perform due to inaccessible superficial veins and thick subcutaneous fat layers. However, successful intravenous drug administration is critical for many biomedical applications including pharmacokinetic studies as extravascular drug administration can influence the drug's absorption and elimination rate. The purpose of this study was to develop and refine an effective technique for indwelling auricular vein catheter placement in the conscious mature sow. We developed a protocol using a topical anesthetic cream and minimal physical restraint to place indwelling catheters in the auricular vein of six multiparous sows. This method was quick (3 min 20 s ± 8 s [mean ± SE per catheter]), effective (11/12 catheters successfully placed) and reliable, allowing a large drug volume (20-22 mL) to be administrated successfully during the trial without relying on prolonged restraint or general anesthesia of the sow.

Age, gender, and earlier opioid requirement associations with the rate of dose escalation in long-term opioid therapy.

OBJECTIVES: To examine the association of risk factors, age, gender, and earlier opioid requirement with the rate of dose escalation in long-term opioid therapy. METHODS: This is a retrospective cohort study of 1,922 individuals identified from California's prescription drug monitoring program database who continuously used opioids from 1999 to 2007. A linear mixed-effects model was used to examine the association of age, gender, and baseline dose requirement with the rate of subsequent opioid dose change. Because of different reporting requirements before and after January 1, 2005, the analyses were conducted separately for patients' opioid use in two periods (6 years between 1999 and 2004 and 3 years between 2005 and 2007). RESULTS: Both the 6-year and the 3-year data showed a significant age association, with younger patients having a higher rate of dose escalation than older patients (p = 0.021 and <0.0001, respectively). Females had a lower rate of dose escalation than males, although the result did not achieve statistical significance in the 6-year data (p = 0.165 and 0.013, respectively). The higher the dose requirement a patient had at baseline, the lower the rate of dose escalation (p < 0.0001 in both periods). CONCLUSIONS: Age, gender, and earlier dose requirement were associated with the rate of dose change in 9-year long-term opioid therapy. Patients aged 75-100 years, being female or having large dose requirement at an earlier stage of therapy may experience a slower dose escalation or even dose decline.

Individual and county-level factors associated with use of multiple prescribers and multiple pharmacies to obtain opioid prescriptions in California.

Use of multiple prescribers and pharmacies is a means by which some individuals misuse opioids. Community characteristics may be important determinants of the likelihood of this phenomenon independent of individual-level factors. This was a retrospective cohort study with individual-level data derived from California's statewide prescription drug monitoring program (PDMP) and county-level socioeconomic status (SES) data derived from the United States Census. Zero-truncated negative binomial (ZTNB) regression was used to model the association of individual factors (age, gender, drug schedule and drug dose type) and county SES factors (ethnicity, adult educational attainment, median household income, and physician availability) with the number of prescribers and the number of pharmacies that an individual used during a single year (2006). The incidence rates of new prescriber use and new pharmacy use for opioid prescriptions declined across increasing age groups. Males had a lower incidence rate of new prescriber use and new pharmacy use than females. The total number of licensed physicians and surgeons in a county was positively, linearly, and independently associated with the number of prescribers and pharmacies that individuals used for prescription opioids. In summary, younger age, female gender, and living in counties with more licensed physicians and surgeons were associated with use of more prescribers and/or more pharmacies for obtaining prescription opioids.

Time series analysis of California's prescription monitoring program: impact on prescribing and multiple provider episodes.

UNLABELLED: Prescription monitoring programs (PMPs) are designed to reduce medication diversion by identifying individuals obtaining the same medication from multiple providers (termed multiple provider episodes [MPEs]). This study determined whether recent changes to California's PMP influenced: 1) the extent that practitioners issue prescriptions for a variety of Schedule II opioids; and 2) the incidence of MPEs involving these opioids. Intervention time series of California's PMP data was used to determine the effect of requiring practitioners to transition from using triplicate prescription forms for Schedule II medications to security forms for all controlled substances. Outcome measures included changes in number of prescriptions issued for Schedule II long-acting or short-acting (SA) opioids and the MPEs involving these medications. Requiring a security form was associated with a sustained prescribing increase for SA hydromorphone, meperidine, and SA oxycodone; no prescribing changes were found for SA fentanyl, methadone, and SA morphine, or for any long-acting opioids. The same policy change, however, increased MPEs involving all opioids. Further effort is required to determine how California's PMP can continue to ensure availability of prescription opioids for medical use while better mitigating their diversion. PERSPECTIVE: Statistical model-building was used to evaluate the influence of changes to California's prescription monitoring program. The extent that practitioners prescribe Schedule II opioids and the incidence of people receiving prescriptions from multiple providers were measured. Such research illustrates the viability of evaluating drug control program impact on prescribing practice and potential diversion behaviors.

An analysis of the number of multiple prescribers for opioids utilizing data from the California Prescription Monitoring Program.

BACKGROUND: Prescription monitoring programs scrutinize the prescribing of controlled substances to diminish the utilization of multiple prescribers (aka. "doctor shopping"). The use of multiple prescribers is not a problem per se and can be legitimate, as when the patient's regular physician is not available or a concurrent painful condition is being cared for by a different practitioner. PURPOSE: The primary objective of this study was to determine if those patients who used a few prescribers (two to five) in a 1-year period were distinguishable from those who used only one prescriber. METHODS: We performed a secondary data analysis of the California Prescription Monitoring Program, the Controlled Substance Utilization Review and Evaluation System, by using data collected during 1999-2007. RESULTS: The group who used a few providers (two to five) differed substantially from those who visited one provider over a 1-year period. However, the dissimilarity did not suggest that these patients were more prone to the abuse of opioids. CONCLUSIONS: The decision not to investigate patients who visit a low number of multiple prescribers (two to five) appears to be justifiable. If the number of providers in a given period of time is used to determine if a patient should be challenged as being a "doctor shopper," cutoffs with high specificity (low false-positive rates) should be chosen. Further epidemiologic research is needed to determine the association of the number of prescribers and misuse and/or abuse of opioids.

Computerized progress notes for chronic pain patients receiving opioids; the Prescription Opioid Documentation System (PODS).

OBJECTIVE: We herein provide a description of a health information technology tool using computer-assisted survey instruments as a methodology for documentation during long-term opioid therapy. DESIGN: We report our experience using the Prescription Opioid Documentation and Surveillance (PODS) System, a medical informatics tool that utilizes validated questionnaires to automate the assessment of opioid prescribing for chronic nonmalignant pain. SETTING AND PATIENTS: Chronic pain patients answered questions that were presented on a computer terminal prior to each appointment in a Department of Veterans Affairs Pain Clinic. MEASURES: Pain levels, activities of daily living, and screening for common psychological disorders were sought at each visit. Results were tabulated with some information gathered sequentially permitting evaluation of progress. Following a face-to-face interview, the clinician added additional comments to the medical record. RESULTS: By deploying a systematic series of questions that are recalled by the computer, PODS assures a comprehensive assessment. CONCLUSIONS: The PODS fulfills medicolegal requirements for documentation and provides a systematic means of determining outcomes. This process facilitates the determination of the appropriate intervals between clinic visits by stratifying patients into high, moderate, and low risk.

Markers of abuse liability of short- vs long-acting opioids in chronic pain patients: a randomized cross-over trial.

BACKGROUND: Abuse liability is thought to possibly be lower in long- than in short-acting opioids because lower peak serum levels may be less likely to induce psychoactive effects. METHODS: We compared patient responses to extended-release morphine, hydrocodone plus acetaminophen, and placebo in a randomized, double-blind crossover study using markers of abuse liability. Patients indicated their craving for drugs on 5 visual analog scales (VASs), completed the Addiction Research Center Inventory, and underwent cue reactivity testing. To perform the latter, subjects watched a video intended to produce a positive or a negative affect, after which a vial of medication was or was not presented (the cue) and then indicated their craving for drugs on 5 different VASs (the reactivity). RESULTS: Differences in Addiction Research Inventory scores were statistically significant but clinically unimportant. Neuropsychological test results were mixed and unrelated to the medications studied. Cue reactivity did not differ among conditions but was uniformly high. CONCLUSIONS: Using several markers of abuse liability, long-acting opioids do not have lower abuse potential than do short-acting opioids or placebo. Although cue reactivity did not differ among the conditions, uniformly high results in these patients suggest that it may have some value as a component of abuse liability testing.

Documenting and improving opioid treatment: the Prescription Opioid Documentation and Surveillance (PODS) System.

OBJECTIVE: To demonstrate that a computer-assisted survey instrument offers an efficient means of patient evaluation when initiating opioid therapy. Design. We report on our experience with the Prescription Opioid Documentation and Surveillance (PODS) System, a medical informatics tool that uses validated questionnaires to collect comprehensive clinical and behavioral information from patients with chronic pain. SETTING AND PATIENTS: Over a 39-month period, 1,400 patients entered data into PODS using a computer touch screen in a Veterans Administration Pain Clinic. MEASURES: Indices of pain intensity, function, mental health status, addiction history, and the potential for prescription opioid abuse were formatted for immediate inclusion into the medical record. RESULTS: The PODS system offers physicians a tool for systematic evaluation prior to prescribing opioids The system generates an opioid agreement between the patient and physician, and provides medicolegal documentation of the patient's condition. CONCLUSIONS: PODS should improve patient care, refine pain control, and reduce the incidence of opioid abuse. Research to determine how PODS affects clinical care is underway. Specially, the effectiveness and efficiency of providing care utilizing PODS will be evaluated in future studies.

A qualitative study of the barriers to chronic pain management in the ED.

PURPOSE: This qualitative study sought to identify perceived barriers to diagnosing and treating patients with chronic pain in the emergency department (ED). BASIC PROCEDURE: Semistructured interviews were conducted with 24 ED physicians from 4 hospitals to elucidate their experiences of managing chronic pain in the ED. MAIN FINDINGS: Time limitations and a low triage priority were major barriers to caring for patients with chronic pain. But despite the inherent problems of treating a nonurgent condition in a time-limited setting, physicians were strong proponents for treating chronic pain in the ED. PRINCIPAL CONCLUSION: Acknowledging that pain can neither be verified nor disproved, physicians tend to err on the side of the patient, often providing an allotment of opioid medications. They also believe that the ED is not an optimal setting for treating patients in chronic pain but that it is often the last resort for many of these patients, thus, providing the rationale for serving them to the best of their ability.

Psychological comorbidities predicting prescription opioid abuse among patients in chronic pain presenting to the emergency department.

OBJECTIVE: We attempted to identify psychological comorbidities that are associated with the propensity for prescription opioid abuse. INTERVENTIONS: Patients presenting to an emergency department seeking opioid refills for chronic pain were evaluated with five validated self-report instruments and structured clinical interviews. The potential for prescription opioid abuse was modeled with multiple regression analysis using depression, anxiety disorders, personality disorder, and addiction as independent variables. RESULTS: Of the 113 patients studied, 91 (81%) showed a propensity for prescription opioid abuse as determined by scores on the Screener and Opioid Assessment for Patients with Pain instrument. Depression, anxiety, and a history of substance were common and panic attacks, posttraumatic stress disorder, and personality disorders were also found, albeit less frequently. Panic attacks, trait anxiety, and the presence of a personality disorder accounted for 38% of the variance in the potential for prescription opioid abuse. CONCLUSIONS: Patients in chronic pain should be assessed for psychological and addiction disorders because they are at increased risk for abusing opioids. They should also be referred for psychosocial treatment as part of their care, where appropriate.

Chronic pain management in the emergency department: a survey of attitudes and beliefs.

OBJECTIVE: The emergency department (ED) can be a particularly challenging environment in which to offer care for chronic pain. This study tried to determine if beliefs held by patients and providers about noncancer-related chronic pain affect evaluation and management of pain in ED. INTERVENTION: We surveyed 103 patients presenting to the ED with chronic pain, 34 ED physicians, and 44 ED nurses to assess the influence of 15 possible barriers to managing chronic pain in the ED. RESULTS: Patients were significantly more likely than providers to believe that their pain had to have a diagnosed physical component to be treated. Providers were significantly more likely than patients to believe that patients came to the ED because they lacked a primary care physician. All agreed that chronic pain treatment was not a priority in the ED and the potential for addiction, dependence, diversion, and forged prescriptions was low. CONCLUSIONS: Patients in chronic pain may need to be reassured that their pain will be treated, even in the absence of objective signs or magnified symptoms. Providers may wrongly believe that lack of a primary care physician brings these patients to the ED. Providers and patients appear to believe that treating chronic pain in the ED has a low priority. Both groups may underestimate the problems inherent with prescribing opioids in this setting.

Circadian variation of the cell proliferation in the jejunal epithelium of rats at weaning phase.

Circadian variation in cell proliferation of the jejunal epithelium of 18-day-old rats was studied using the 2-h arrested metaphase score and crypt isolation method. A continuous decrease in the arrested metaphases occurred from 07.00 h to 13.00 h. From 17.00 h arrested metaphase values increased and were maintained at the higher level during the dark period as showed by Cosinor analyses (P < 0.05). These results indicate that in the young rat there is already a circadian variation in jejunal epithelial cell proliferation as early as 18 days. We can even suggest that the presence of a circadian rhythm at weaning contributes to the steady state of cell proliferation in the intestinal epithelium observed in adult life.