Pain Management Stewardship Programs, Part I: A Review of Legislative and Regulatory Changes.

Background: Opioid use is classified as an epidemic by many due to the impact of these medications on society. Federal and state laws for prescribing and dispensing opioids have changed rapidly in a short period of time to hopefully balance proper pain control with their use. Pharmacy directors must be informed of these rapid changes to effectively work as part of any opioid stewardship team. Objective: The objective of this study was to provide foundational leadership guidance to pharmacy directors on current opioid legislation, literature, and best practices to assist in improving opioid use. Methods: A review of the literature from 2003 to the present was conducted along with collating important up to date resources and other publications that provide foundational information to help support a comprehensive management of opioid use. A summary of these data has been collated into an easy to use table and summarized throughout this article. Conclusion: The information provided in this article helps to properly inform pharmacy leaders to the resources available to improve the prescribing, dispensing, and monitoring of opioids and alternatives.

Use of Continuous Renal Replacement Therapy for Removal of Dabigatran in a Patient in Need of Emergent Surgery.

Purpose. To report the ability to remove serum dabigatran using continuous renal replacement therapy (CRRT) in a patient with life-threatening bleeding. Summary. A 77-year-old female with history of atrial fibrillation who takes dabigatran for stroke prevention presented with abdominal pain. Patient was found to have bleeding and possible mesenteric ischemia and was taken to the operating room and had continued bleeding postoperatively. CRRT was initiated for the removal of any remaining dabigatran, with serum dabigatran levels collected to evaluate removal of dabigatran with CRRT. This patient had an increased dabigatran level prior to intervention, which decreased to an undetectable level after use of CRRT. Greater than 80% of the drug was removed due to 4 hours of CRRT and residual kidney function. Reversal of dabigatran is an area of current research with recent FDA approval of idarucizumab for use. Conclusion. Bleeding may occur as a result of the use of dabigatran and change in patient's clinical condition. Use of CRRT may be an option in removing serum dabigatran in the case of a life-threatening bleed.

Risk factors for venous thromboembolism in patients with chronic liver disease.

BACKGROUND: Pharmacologic prophylaxis for venous thromboembolism (VTE) in patients with chronic liver disease (CLD) presents a unique challenge because of coagulopathies associated with the disease. When evaluating whether these patients require VTE prophylaxis upon hospitalization, it would be advantageous if risk factors for the development of VTE in this population were known. OBJECTIVE: To evaluate risk factors associated with the development of VTE in patients with CLD. METHODS: A retrospective case-control study was conducted. Patients admitted to the University of Kentucky Chandler Hospital from October 2006 to July 2010 with a diagnosis of CLD and VTE were matched in a 1:3 fashion with CLD patients without VTE. The primary objective was to determine whether there were significant differences in laboratory values between the 2 groups. RESULTS: During this time, 27 patients with CLD (1.0%) were diagnosed with VTE. These patients had significantly lower median aspartate aminotransferase (AST) (47 vs 70 U/L, p = 0.04), alanine transaminase (ALT) (24.5 vs 36 U/L, p = 0.02), albumin (2.1 vs 2.4 g/dL, p = 0.02) and hematocrit (Hct) (28.3% vs 32%, p = 0.03) values compared to the control patients. Patients with albumin lower than 1.9 g/dL had a 5.1 times greater risk of VTE compared to patients with albumin of 2.8 g/dL and higher (OR 5.14, 95% CI 1.05-25.2). CONCLUSIONS: Patients with CLD who developed VTE had significantly lower AST, ALT, albumin, and Hct compared to those of control patients. Studies are necessary to further examine the significance of this finding.

Preventing the harm of a closer look: contrast-induced nephropathy in adults.

Contrast media is administered to many patients in hospitals nationwide. Although the use of contrast and dyes is widespread and has a well accepted use among the medical profession, contrast-induced nephropathy can be a common and potentially harmful complication. Identifying patients at risk, attempting to minimize risk, and using preventative strategies should be priorities to decrease the harmful effects that are associated with the administration of contrast media. This article provides a general overview of contrast-induced nephropathy and a brief review of the risk factors and prophylactic treatment.

A clinical-laboratory algorithm incorporating optical density value to predict heparin-induced thrombocytopenia.

The diagnosis of heparin-induced thrombocytopenia (HIT) is complex and involves integrating both clinical and laboratory findings. Readily available diagnostic tests such as the heparin-dependant antibody assay (HDAA) lack desired specificity when utilised alone. A diagnostic algorithm incorporating the 4T pretest probability score, HDAA, and optical density (OD) value was implemented as a tool to assist in the diagnosis of HIT and with the decision to treat patients. Patients with a 4T score >3 and/or positive HDAA result with an OD ≥1 were considered positive. Utilisation of this algorithm was hypothesised to improve the identification of patients without SRA confirmed HIT and improve overall specificity compared to other diagnostic strategies. Retrospective chart review was conducted and included patients with a positive or equivocal HDAA result and a serotonin release assay result during a two-year period. Each patient was evaluated for the diagnosis of HIT using the algorithm. The specificity and sensitivity of the diagnostic algorithm to identify subjects with SRA confirmed HIT was evaluated. A total of 83 patients were identified for inclusion in the study. The diagnostic algorithm identified 22 patients for direct thrombin inhibitor (DTI) therapy. Nine of these patients were SRA positive. The sensitivity of the algorithm was 0.9 with a specificity of 0.822. The diagnostic algorithm was found to be both more specific and sensitive than other diagnostic strategies including the 4T score alone, HDAA alone, and the combination of the 4T score and HDAA results. This preliminary data suggest a diagnostic algorithm combining 4T score, HDAA, and OD value may be a tool to aid in the identification SRA positive patients for DTI therapy.

Evaluation of a clinical scoring scale to direct early appropriate therapy in heparin-induced thrombocytopenia.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a serious adverse effect associated with heparin therapy. Current laboratory confirmation for immune mediated HIT often results in false positives and unnecessary treatment, exposing individuals to possible complications. As a result, clinical evaluation has been recommended in conjunction with laboratory testing. We hypothesize that utilization of a clinical scoring scale, the 4T's, will result in the initial appropriate therapy for suspected HIT. METHODS: This is a retrospective chart review of 108 patients who underwent ELISA testing for HIT at a university hospital. The 4T's scale was applied, stratifying individuals into low, intermediate, and high-risk categories. Each risk score was compared to the ELISA results to determine if the 4T's can predict the diagnosis of HIT and result in appropriate management. ELISA optical density scores as well as incidence of adverse events were also compared among risk categories. STUDY RESULTS: Individuals with low risk correlate with a negative ELISA compared to intermediate and high-risk individuals (p = 0.01 and p<0.01) and also were significantly more likely to predict institution of appropriate therapy (p<0.01). Median optical density scores were 0.184 (0.046-2.116), 0.226 (0.067-1.887), and 0.476 (0.096-1.309) for low, intermediate, and high 4T scores. Major adverse events include thrombosis and bleeding. CONCLUSIONS: Individuals with low risk were more likely to receive initial, appropriate therapy and were also significantly more likely to have a negative ELISA test result. Individuals with low risk determined by the 4T score therefore may have therapy and serologic testing for HIT withheld.

Effects of hyperglycemia on the development of new-onset diabetes after liver transplantation.

CONTEXT: New-onset diabetes after transplantation (NODAT) has been associated with cardiovascular and thrombotic complications, acute rejection, and infection in transplant recipients. NODAT in kidney transplantation is well described; however, data are lacking in liver transplant recipients. OBJECTIVE: To evaluate the incidence of new-onset diabetes within 6 months postoperatively in adult liver transplant recipients. DESIGN, PARTICIPANTS, SETTING, AND INTERVENTIONS: Patients who underwent a liver transplantation at our institution between January 2004 and December 2005 were retrospectively evaluated. NODAT was defined according to the diagnostic criteria of the American Diabetes Association/World Health Organization, persistent hyperglycemia (serum glucose > or = 200 mg/dL occurring 2 weeks after initial steroid induction and persisting for more than 2 weeks), or the need for hypoglycemic agents upon discharge. MAIN OUTCOMES: Incidence of NODAT within 6 months after transplantation in patients with poor glycemic control within the first 2 weeks after transplantation, acute rejection episodes, infections, hospital readmissions, and cardiovascular and thrombotic events. RESULTS: Forty-five patients were evaluated. Within the first 6 months after transplantation, NODAT developed in 11 (24%). Acute rejection, infection, hospital readmissions, cardiovascular events, and thrombotic events did not differ between the groups. CONCLUSION: Elevated fasting levels of blood glucose during the first 2 weeks after liver transplantation may be associated with an increased incidence of NODAT and may have predictive value. More studies are needed to determine the effects of recognition and treatment of hyperglycemia in recent transplant recipients.

Effects of a pharmacist-to-dose computerized request on promptness of antimicrobial therapy.

OBJECTIVES: To examine the effects of computerized requests for pharmacist-to-dose (PTD), an advanced clinical decision support tool for dosing guidance, on antimicrobial therapy with vancomycin and aminoglycosides, describe PTD request utilization, and identify factors that may prolong this process. DESIGN: A retrospective review was conducted of patients hospitalized from Jan 2004 to Jun 2006 with suspected pneumonia who received vancomycin, tobramycin, or gentamicin via PTD (study) or routine provider order entry (control). MEASUREMENTS: The primary endpoint was time to pharmacist completion of PTD request. Secondary data points included medication turn-around times for first doses of vancomycin or aminoglycosides and for first doses of any antibiotic, dose adjustment for renal dysfunction, medication errors, and time of order entry. Multivariate analysis was conducted to identify predictors of total time to pharmacist verification and time to administration of first doses of vancomycin or aminoglycosides. RESULTS: Median time for pharmacist completion of PTD requests was 29 minutes. Delays were noted in the study group (n = 49) by comparison with the control group (n = 48) for median time to first dose of vancomycin or aminoglycoside (185 vs. 138 min, p = 0.45) and for any antibiotic (134 vs. 118 min, p = 0.42), respectively. Fewer medication errors were reported in the study group (5 vs. 18 errors, p = 0.002). In a multivariate model, PTD was not significantly predictive of time to pharmacy verification or medication turn-around time. CONCLUSIONS: Pharmacists completed pharmacist-to-dose consultations for dosing guidance of vancomycin and aminoglycosides within a median of 30 minutes. Implementation of a computerized request for clinical pharmacists to provide medication-related clinical decision support increased medication turn-around time of vancomycin and aminoglycosides and reduced medication errors. Consultation of clinical pharmacists by computerized request for initial antibiotic dosing of medications with narrow therapeutic windows is an option for medication-related clinical decision support but providers should be aware that consultation may delay medication turn-around time.

Drug selection in a patient with a history of hypersensitivity reactions: a practical approach for the orthopedist.

Drug allergies are specific to characteristics of the medication's chemical structure.

An institutional process to improve inpatient glycemic control.

Many institutions are evaluating their inpatient patterns of care for patients with diabetes mellitus and hyperglycemia, based upon compelling evidence that strict glycemic control improves outcomes in a variety of hospital settings. In 2005, a multidisciplinary task force was established at the University of Kentucky Chandler Medical Center in Lexington, Kentucky, to guide a process to improve the quality and safety of inpatients with hyperglycemia. This article describes the stepwise process including an examination of our procedures, adoption of standards, and establishment of common protocols and procedures. Successful implementation of the protocols was preceded by extensive educational efforts. Refinement of the protocols based on early experience and feedback from staff has resulted in improvements in glycemic parameters and less reliance on sliding scale insulin regimens.

Fondaparinux as a treatment option for heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated complication that can occur after exposure to heparin products. Because patients with HIT are at increased risk for thrombosis, anticoagulation is warranted. The direct thrombin inhibitors lepirudin and argatroban are approved by the United States Food and Drug Administration (FDA) for this indication. Bivalirudin, another direct thrombin inhibitor, is approved for use in patients with HIT who must undergo percutaneous coronary intervention. The synthetic pentasaccharide fondaparinux lacks FDA approval for treating patients with HIT; however, a few published reports describe its use. Furthermore, various small-scale, in vitro studies have demonstrated a lack of cross-reactivity between fondaparinux and HIT antibodies. Large, in vivo comparison trials must be performed before fondaparinux can become a standard treatment option in the setting of HIT.

Pharmacy resident participation in cardiopulmonary resuscitation events.

PURPOSE: An electronically administered cross-sectional survey was conducted to establish the rate of pharmacy resident participation in cardiopulmonary resuscitation (CPR) events at pharmacy residency programs throughout the United States and Puerto Rico. METHODS: A 46-item questionnaire was developed and sent by e-mail to pharmacy residency program directors. The recipients were given one month to complete the survey. Responses were screened for duplicate answers, and the most complete survey was included in the analysis. The survey dealt with residency program demographics and sought information about required life-support certifications for pharmacy personnel, institution-specific training methods for medical emergencies employed by pharmacy departments, responsibilities of pharmacy personnel who respond to CPR events, and evaluation methods used to assess resident performance in CPR events. RESULTS: A total of 745 pharmacy residency directors were surveyed. Responses were received from 190 residency program directors, which represented 221 residency programs. The three most common residency program settings were community (not-for- profit) hospitals, college and university hospitals, and government hospitals. Thirty percent of respondents required pharmacy resident response to CPR events, while 38% made this opportunity optional. In 85% of programs that required or offered resident response to CPR events, there was a formal CPR team. The three primary roles fulfilled by pharmacists in medical emergencies were provision of drug information, drug admixture, and documentation; pharmacy resident duties mirrored these roles. CONCLUSION: Pharmacy resident response to CPR events was required in approximately 30% of responding pharmacy residency programs. Various methods were used in educating, assessing, and evaluating pharmacy residents in this role.

Clinical utility of a continuous intravenous infusion of valproic acid in pediatric patients.

STUDY OBJECTIVE: To describe the dose-concentration relationship of a continuous intravenous infusion of valproic acid (VPA) in pediatric patients when a dosing protocol is used. DESIGN: Retrospective and concurrent chart review. SETTING: Tertiary care, 473-bed, academic medical center with a 120-bed, dedicated children's hospital. PATIENTS: Twenty-six pediatric patients (< 18 yrs old) who received VPA according to the protocol for continuous intravenous infusions between January 1, 2004, and March 31, 2006, identified by using a pharmacy order-entry system. MEASUREMENTS AND MAIN RESULTS: Patient demographics, VPA treatment regimens, clinical responses, and safety data were recorded and analyzed. Median patient age was 8.5 years (range 1.4-16 yrs). Approximately two thirds received VPA for seizures, and one third for migraines. Patients were given a mean +/- SD VPA loading dose of 28.5 +/- 5.2 mg/kg followed by a continuous infusion rate of 1 +/- 0.2 mg/kg/hour. Mean +/- SD serum concentration measured 4.5 +/- 1.6 hours after the loading dose was 83.3 +/- 22.8 microg/ml. Steady-state concentration at 23.3 +/- 3.0 hours after the start of the continuous infusion was 80.0 +/- 26.0 microg/ml. Postload and steady-state serum concentrations were within the target concentration of 50-100 microg/ml in 77% and 69% of patients, respectively. On further analysis, when the target range was expanded to 50-125 microg/ml (125 microg/ml was deemed acceptable if no adverse effects were noted), 89% and 92% of patients, respectively, had postload and steady-state VPA serum concentrations within this range. The response rate was excellent, with nearly 85% of patients achieving a complete or partial response to therapy. Adverse effects were generally mild and uncommon. CONCLUSIONS: The continuous-infusion protocol permitted rapid intravenous loading of VPA in pediatric patients while minimizing adverse events and achieving concentrations in the upper region of the therapeutic range.

EEG alpha sensitization in individualized homeopathic treatment of fibromyalgia.

Fibromyalgia (FM) patients show evidence of sensitizability in pain pathways and electroencephalographic (EEG) alterations. One proposed mechanism for the claimed effects of homeopathy, a form of complementary medicine used for FM, is time-dependent sensitization (TDS, progressive amplification) of host responses. This study examined possible sensitization-related changes in EEG relative alpha magnitude during a clinical trial of homeopathy in FM. A 4-month randomized, placebo-controlled double-blind trial of daily orally administered individualized homeopathy in physician-confirmed FM, with an additional 2-month optional crossover phase, included three laboratory sessions, at baseline, 3 and 6 months (N = 48, age 49.2 +/- 9.8 years, 94% women). Nineteen leads of EEG relative alpha magnitude at rest and during olfactory administration of treatment and control solutions were evaluated in each session. After 3 months, the active treatment group significantly increased, while the placebo group decreased, in global alpha-1 and alpha-2 during bottle sniffs over sessions. At 6 months, the subset of active patients who stayed on active continued to increase, while the active-switch subgroup reversed direction in alpha magnitude. Groups did not differ in resting alpha. Consistent with the TDS hypothesis, sniff alpha-1 and alpha-2 increases at 6 months versus baseline correlated with total amount of time on active remedy over all subjects (r = 0.45, p = .003), not with dose changes or clinical outcomes in the active group. The findings suggest initiation of TDS in relative EEG alpha magnitude by daily oral administration of active homeopathic medicines versus placebo, with laboratory elicitation by temporolimbic olfactory stimulation or sniffing.

Reduced leptin concentrations are permissive for display of torpor in Siberian hamsters.

A photoperiod with a short photophase induces a winterlike phenotype in Siberian hamsters that includes a progressive decrease in food intake and body mass and reproductive organ regression, as well as reversible hypothermia in the form of short-duration torpor. Torpor substantially reduces energy utilization and is not initiated until body mass, fat stores, and serum leptin concentrations are at their nadir. Because photoperiod-dependent torpor is delayed until fat reserves are lowest, leptin concentrations may be a permissive factor for torpor onset. This conjecture was tested by implanting osmotic minipumps into Siberian hamsters manifesting spontaneous torpor; the animals received a constant release of leptin or vehicle for 14 days. Exogenous leptin treatment eliminated torpor in a significant proportion of treated hamsters, whereas treatment with the vehicle did not. Similarly, endogenous serum leptin concentrations were markedly reduced in all animals undergoing daily torpor. Although simply reducing leptin concentrations below a threshold value is not sufficient for torpor initiation, reduced leptin concentrations nevertheless appear necessary for its occurrence. It is proposed that drastically reduced leptin concentrations provide a "starvation signal" to an as yet unidentified central mechanism mediating torpor initiation.

Individual differences in response to randomly assigned active individualized homeopathic and placebo treatment in fibromyalgia: implications of a double-blinded optional crossover design.

OBJECTIVE: To assess individual difference characteristics of subgroups of patients with fibromyalgia (FM) patients with respect to the decision to stay in or switch from randomly-assigned verum or placebo treatment during an optional crossover phase of a double-blinded homeopathy study. DESIGN: Double-blinded, randomized, placebo-controlled, optional crossover clinical trial. PARTICIPANTS: Fifty-three (53) community-recruited patients with FM entered the optional crossover phase. INTERVENTION: Two homeopaths jointly selected an individualized homeopathic remedy for all patients. The pharmacy dispensed either verum LM remedy or indistinguishable placebo in accord with randomized assignment for 4 months and the patient's optional crossover decision for an additional 2 months. OUTCOME MEASURES: Patients completed a battery of baseline state/trait questionnaires, including mood, childhood neglect and abuse, and trait absorption. They rated global health (whole person-centered) and tender point pain on physical examination (disease-specific) at baseline, 3 months, and 6 months. RESULTS: Rates of optional crossover from verum to placebo or placebo to verum were comparable (p = 0.6; 31%, and 41%, respectively). The switch subgroups had greater baseline psychologic issues (emotional neglect in placebo-switch; depression and anger in verum-switch). The verum-stay subgroup scored highest on treatment helpfulness and included all six exceptional responders who fell, prior to crossover, into the top terciles for improvement in both global health and pain. Patients staying in their randomly assigned groups, active or placebo (n = 34), scored significantly higher in trait absorption than did those who switched groups (n = 19). CONCLUSION: Individual difference factors may predict better and poorer responders with FM to specific and nonspecific effects of homeopathic and placebo treatment.

Electroencephalographic cordance patterns distinguish exceptional clinical responders with fibromyalgia to individualized homeopathic medicines.

OBJECTIVES: To characterize initial central nervous system responses to olfactory administration of homeopathic remedies as biomarkers for subsequently exceptional, simillimum-like clinical outcomes at a systemic level (i.e., both locally and globally). DESIGN: Double-blinded, randomized, placebo-controlled clinical trial. SETTING: A private homeopathic clinic in Phoenix, AZ, and a university laboratory in Tucson, AZ. PATIENTS: Sixty-two (62) persons with physician-confirmed fibromyalgia (FM) (mean age, 49 years; 94% women) enrolled; 53 completed the 3-month assessment visit. Exceptional responders (n = 6, 23% of active treatment group; none on placebo) were those with improvements in the top one-third for both tender point pain and global health ratings after 3 months. INTERVENTION: Patients took daily oral doses of treatment solution in LM (1/50,000 dilution) potency (active group received individualized remedy; placebo group received plain solvent). Dependent measures: Baseline and 3-month difference scores for initial prefrontal electroencephalographic alpha frequency cordance (EEG-C, a correlate of functional brain activity) during 16 pairs of randomized, double-blinded bottle sniffs (treatment minus control solutions). RESULTS: Exceptional responders versus other patients exhibited significantly more negative initial EEG-C difference scores at prefrontal sites. Right prefrontal cordance findings correlated with subsequently reduced pain (r = 0.85, p = 0.03), better global health (r =-0.73, p = 0.10), and trait absorption (genetically determined ability to focus attention selectively and fully) (r = 0.91, p = 0.012). CONCLUSIONS: These observations suggest prefrontal EEG-C as an early biomarker of individualized homeopathic medicine effects in patients with FM who later exhibit exceptional outcomes. Prefrontal cortex controls executive function, including ability to redirect attention. Interactions between executive function, absorption, and the simillimum remedy could facilitate exceptional responses.