Biomedical subjects
Publications and source records attributed to M A Ashburn.
Advances in biopharmaceutical technology have spawned new drug delivery devices and mechanisms. Noninvasive methods, including iontophoresis and transmucosal drug delivery, have improved treatment of certain patient population. Their use is discussed in the following paper.
This study evaluated the effect of locally applied heat on the transdermal delivery of testosterone. Six healthy adult volunteers were tested three times while receiving a 5 mg androgen patch, the same patch with a heat-generating patch, and no patch at all over 12 hours. Statistically significant differences in mean maximum serum testosterone concentration values were seen. Heat plus patch resulted in a mean maximum serum testosterone concentration of 939 ng/dl versus 635 ng/dl (patch only) and 425 ng/dl (no patch). (Heat + patch vs. no patch: p < 0.001; heat + patch vs. patch: p < 0.001; patch vs. no patch: p = 0.003.) The area under the curve of plasma testosterone concentration versus time values were means of 4114 ng/dl.h versus 1985 ng/dl.h for the patch-only group (p = 0.001). The use of heat improved absorption of transdermal testosterone and decreased time to peak serum testosterone concentrations, resulting in a statistically significant difference in mean maximum serum testosterone concentrations compared with the use of the patch without heat.
The growing burden of regulations and statutes that physicians in the United States must comply with has become an inescapable aspect of the practice of medicine. With the advent of this heightened regulation has also come a new governmental commitment to discover and punish fraud and abuse in the practice of medicine. It is thus incumbent upon pain practitioners to be aware of the basic principles in fraud and abuse law so as to avoid obvious situations of legal liability and to know when to seek expert legal advice in the structuring of business transactions affecting their practice.
OBJECTIVES: To examine the effects of locally applied heat on the systemic delivery of fentanyl through the Transdermal Fentanyl Delivery System. DESIGN: Open, 2-period crossover randomized study conducted in the anesthesia department of a university teaching hospital. METHOD: Six healthy adult volunteers received a fentanyl 25-microg/h patch with and without local heat for 240 minutes followed by administration without heat for an additional 20 hours. Participants then crossed over. Venous blood was drawn at baseline and hourly for 24 hours. Peak plasma concentration (CMax) of fentanyl was measured and the area under the curve (AUC) of the plasma fentanyl concentration versus time post administration graph was evaluated. RESULTS: Difference in CMax and AUC were not statistically significant over the entire 24-hour study period. However, for the 4-hour period of heat application statistically significant differences were seen in both mean CMax (heat, 0.4 ng/mL versus no heat, 0.1 ng/mL (P =.030)) and mean AUC (heat, 40 ng/mL x min versus no heat, 10 ng/mL x min (P =.010)). CONCLUSION: Local heat can speed the onset of steady state fentanyl concentration in the Fentanyl Transdermal Drug Delivery System thus limiting the delay in onset of analgesia and allowing earlier identification and treatment of side effects.
OBJECTIVE: To assess the reliability of an augmented SF-36 instrument, the Treatment Outcomes in Pain Survey ("TOPS"), in patients treated in two pain management programs, and present norms for initial values and treatment-related improvements. DESIGN: Prospective case series at two sites with longitudinal follow-up. SETTING: Multidisciplinary, comprehensive outpatient pain treatment centers in university hospitals in Salt Lake City and Boston. PATIENTS: Nine hundred and forty seven adult outpatients with a range of socioeconomic, demographic, and ethnic characteristics, all referred for evaluation and treatment of chronic pain. INTERVENTIONS: Usual practice multidisciplinary pain treatment. OUTCOMES MEASURES: TOPS prior to pain treatment and 5-week nominal follow-up. Means and standard deviations of baseline and follow-up results. Psychometric results for reliability (Cronbach alpha), validity (item discriminant validity, validity coefficients), and related statistical precision measures for group and individual designs. RESULTS: Several measures were precise enough to permit following individual patients in standard clinic treatment, of which the Total Pain Experience dimension was the most powerful. Similar psychometrics were observed in the Boston and Salt Lake City sites. The Pain Symptom, Objective Family/Social Disability, Objective Work Disability, and Upper Body Functional Limitations scales were validated. DISCUSSION: The TOPS was designed to satisfy several models of clinical pain treatment. It successfully monitored treatment based on those models. Not all patients improve with treatment, but most do. The TOPS can be administered in a variety of ways, but we found paper and pencil administration with computer scanning of results quick and efficient for making the data available to clinicians as part of treatment. CONCLUSIONS: The accuracy of the TOPS is sufficient to monitor the response of individual patients during multidisciplinary treatment of chronic pain. The TOPS provides needed documentation (e.g., to third-party payors) of the aggregate value of multidisciplinary outpatient treatment of chronic pain as well as its benefit for individual patients.
Accurate and sensitive communication of health care information is essential to effective patient management in the pain clinic, operating room, other health care settings. However, information relating to the health care status of a patient is sensitive and may be embarrassing or damaging if it falls into the wrong hands. Ethical cannons of medicine and statutory provisions have emphasized the obligation of the physician to safeguard patient confidences. However, threats to the confidentiality of medical information abound and are even more significant in our age of instantaneous communication characterized by the growing use of email, facsimile, and the Internet. This article outlines legal issues relating to communication in three key areas of health care law: confidentiality/breach of privacy, informed consent, and defamation. The major principles of the law in these areas are discussed and case studies are used to illustrate key points and give simple preventive strategies to help steer the delicate balance between sharing important healthcare information and protecting sensitive patient information.
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BACKGROUND: Oral transmucosal fentanyl citrate (OTFC) is a solid form of fentanyl that delivers the drug through the oral mucosa. The clinical utility of multiple doses of OTFC in the treatment of "breakthrough" cancer pain is under evaluation. The aim of this study was to test the hypothesis that the pharmacokinetics of OTFC do not change with multiple dosing. METHODS: Twelve healthy adult volunteers received intravenous fentanyl (15 microg/kg) or OTFC (three consecutive doses of 800 microg) on separate study sessions. Arterial blood samples were collected for determination of fentanyl plasma concentration by radioimmunoassay. The descriptive pharmacokinetic parameters (maximum concentration, minimum concentration, and time to maximum concentration) were identified from the raw data and subjected to a nonparametric analysis of variance. Population pharmacokinetic models for all subjects and separate models for each subject were developed to estimate the pharmacokinetic parameters of fentanyl after multiple OTFC doses. RESULTS: The shapes of the profiles of plasma concentration versus time for each dose of OTFC were grossly similar. No change was noted for maximum concentration or time to maximum concentration over the three doses, while minimum concentration did show a significantly increasing trend. Terminal half-lives for intravenous fentanyl and OTFC were similar. A two-compartment population pharmacokinetic model adequately represented the central tendency of the data from all subjects. Individual subject data were best described by either two- or three-compartment pharmacokinetic models. These models demonstrated rapid and substantial absorption of OTFC that did not change systematically with time and multiple dosing. CONCLUSIONS: The pharmacokinetics of OTFC were similar among subjects and did not change with multiple dosing. Multiple OTFC dosing regimens within the dosage schedule examined in this study can thus be formulated without concern about nonlinear accumulation.
OBJECTIVE: The objective of this study was to evaluate the depth and duration of skin anesthesia after the administration of a local anesthetic system consisting of an S-Caine (Zars, Salt Lake City, UT) patch coupled with a controlled heat-aided drug delivery (CHADD; Zars) patch. DESIGN: The study design was a randomized, double-blind, placebo-controlled, two-period crossover trial. PATIENTS: Twelve healthy adult volunteers between the ages of 18 and 50 years were enrolled. INTERVENTIONS AND OUTCOME MEASURES: After administration of the study drug or placebo, vital signs (blood pressure, pulse, respiratory rate) were monitored and recorded, and depth and duration of anesthesia were determined and recorded at defined intervals for 10 to 120 minutes after treatment. Depth of anesthesia was measured with a 21-gauge short-bevel needle attached to a depth gauge, and duration was measured using a 0 to 2 (0 = no sensation, 1 = dull sensation, 2 = sharp scratching sensation) verbal report scale. RESULTS: Statistically significant differences were noted in both depth and duration of anesthesia between the active and placebo groups. The posttreatment mean for anesthetic depth in the active group was 6.8 mm compared with 4.7 mm for control group (p = 0.050). The median anesthetic duration was greater than 120 minutes for the active group compared with less than 10 minutes for the placebo group (p = 0.001). CONCLUSIONS: The local anesthetic system consisting of a combination of S-Caine and CHADD patches provided a statistically significant dermal anesthesia effect compared with placebo in this volunteer study. If confirmed in other studies, this system has promise as a noninvasive method of producing dermal anesthesia for minor surgical procedures or intravenous insertion.
Chronic pain is a common condition for which patients seek care from various health-care providers. This type of pain causes much suffering and disability and is frequently mistreated or undertreated. Patients who present for evaluation for chronic pain should undergo a careful assessment before therapy. Patients with chronic pain commonly experience depression, sleep disturbance, fatigue, and decreased overall physical and mental functioning. They frequently require an interdisciplinary model of care to allow care givers to address the multiple components of the patient's pain experience. After a careful evaluation, therapy may include medication, nerve blocks, active physical therapy, behavioural interventions, and assistance with vocational evaluation and training. Less frequently therapy may include placement of implantable devices to alter the pain experience. These patients suffer from a chronic condition and often require long-term care, with frequent reassessment and adjustment of therapy. Although cure is possible, it is also infrequent. Therefore, therapy is provided with the aim of decreasing pain and suffering while improving physical and mental functioning.
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OBJECTIVE: The primary objective was to evaluate the clinical safety and effectiveness of the iontophoretic administration of lidocaine HCl 2% and epinephrine 1:100,000 to induce local dermal anesthesia before intravenous (i.v.) cannulation. DESIGN: Section I: Open, nonblinded. Section II: Randomized, double-blind, placebo-controlled. SETTING: Section I: Healthy adult volunteers. Section II: Patients presenting for scheduled outpatient eye surgery. PATIENTS: Section I: Seven healthy adult volunteers. Section II: Forty-four patients requiring i.v. cannulation before scheduled eye surgery. INTERVENTIONS: Section I: Volunteers received iontophoresis of lidocaine HCl 2% with epinephrine 1:100,000 for a total delivery current of 40 mA min. Section II: Patients received iontophoresis for a total delivery current of 40 mA min of lidocaine HCl 2% with epinephrine 1:100,000 (active) or saline (control) immediately before intravenous cannulation with a 20-gauge i.v. catheter. MAJOR OUTCOME MEASURES: Section I: Venous blood plasma lidocaine levels, adverse events associated with iontophoresis. Section II: Patient and investigator assessment of analgesia, patient acceptance of iontophoresis, adverse events associated with iontophoresis. RESULTS: Section I: No detectable levels of lidocaine were identified in any blood plasma sample. Adverse effects were minimal and transitory. Section II: Pain was decreased following lidocaine iontophoresis in comparison with controls, as determined by the patients and investigators. Iontophoresis was well accepted by the patients. Adverse effects were minimal and transitory. CONCLUSIONS: Iontophoresis of lidocaine 2% with 1:100,000 epinephrine for short delivery times does not lead to delivery of clinically important systemic levels of lidocaine in healthy adults. Iontophoresis of lidocaine 2% with 1:100,000 epinephrine provides adequate skin anesthesia for placement of peripheral small-gauge i.v. catheters.
Combined spinal epidural anesthesia has become increasingly popular as a method of providing rapid onset of analgesia or surgical block with access for further administration of analgesics or anesthetics. No in vivo studies have evaluated the relationship between dural puncture and drug transfer from the epidural space to the cerebrospinal fluid (CSF). To determine whether morphine administered in the epidural space adjacent to a dural puncture results in increased CSF concentrations at the cisterna magna (CM), 12 adult ewes were studied. Each animal was assigned to one of three groups. Animals in Group 1 served as a control and received no dural puncture. Animals in Group 2 received a dural puncture with a 25-gauge (G) Whitacre needle, while Group 3 animals received a dural puncture with an 18-G Tuohy needle. One hour after dural puncture, each animal was given epidural morphine, 0.2 mg/kg. Six hours after the administration of epidural morphine, CSF from the CM was sampled and analyzed by gas chromatography-mass spectrometry for morphine concentration. The mean morphine concentration at the CM for Group 1 (control) was 22 +/- 12 ng/mL, whereas animals with 25-G and 18-G dural punctures had concentrations of 154 +/- 32 ng/mL and 405 +/- 53 ng/mL, respectively (P = 0.0005). These data demonstrate that a significant increase in CSF morphine concentration at the brainstem will occur when lumbar epidural morphine is administered adjacent to a dural puncture. Furthermore, the increase in CSF morphine concentration is positively correlated with the size of the needle producing the dural puncture. These findings highlight the potential for delayed respiratory depression when epidural opiate administration follows a dural puncture.
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BACKGROUND: Iontophoresis is a method of transdermal administration of ionizable drugs in which the electrically charged components are propelled through the skin by an external electric field. This study was designed to determine whether iontophoresis could be used to deliver clinically significant doses of fentanyl in humans and whether there is a charge-dose relation in the delivery of fentanyl by iontophoresis. METHODS: Five adult volunteers were tested three times on separate days, once receiving passive treatment of 0.0 mA for 2 h (0 mA.min), iontophoresis 1.0 mA for 2 h (120 mA.min), and iontophoresis 2.0 mA for 2 h (240 mA.min) in an open, randomized, crossover design. Respiratory rate, heart rate, blood pressure, and hemoglobin oxygen saturation were monitored throughout the study. Plasma fentanyl concentrations were measured several times before, during, and after iontophoresis. Plasma fentanyl concentrations were measured by radioimmunoassay. RESULTS: No fentanyl was detected after passive (0.0-mA) fentanyl delivery. The following results were obtained for the 1.0- and 2.0-mA deliveries, respectively. Mean times to detectable concentrations of plasma fentanyl were 33 and 19 min; mean times to maximum concentration were 122 and 119 min; maximum concentrations were 0.76 and 1.59 ng/ml (P = 0.010); mean areas under the curve of the plasma fentanyl concentration versus time relation were 233 and 474 ng.ml-1.min (P = 0.003); and mean elimination half-lives were 354 and 413 min (P = 0.326). Only minor adverse side effects related to iontophoresis occurred. However, typical opioid-related effects occurred frequently in the 1.0- and 2.0-mA administration groups. CONCLUSIONS: Clinically significant doses of fentanyl can be administered by iontophoresis for delivery periods of 2 h. A charge-dose relation exists after administration with currents of 1.0 and 2.0 mA. Future research into the iontophoresis of fentanyl as a method of potent opioid administration is indicated.
OBJECTIVE: The objective of this study was to identify the underlying causes of respiratory-related critical events associated with intravenous patient-controlled analgesia (i.v. PCA). DESIGN: The design is an observation study of prospectively collected data. SETTING: An Acute Pain Service (APS) was established for the management of all patients receiving i.v. PCA therapy for pain management. As part of ongoing care, all respiratory-related critical events were documented and analyzed by staff members of the APS team. PATIENTS: All patients receiving i.v. PCA therapy through the APS during the period of May 1990 through October 1992 were enrolled in the study. INTERVENTIONS: Evaluation of all respiratory-related critical events was attempted to identify the underlying cause of the event and to determine if measures could be taken to prevent recurrence of similar events. OUTCOME MEASURES: Any clinical event that could have or did lead to adverse patient outcome was used as an outcome measure. RESULTS: A total of 3,785 patients received PCA therapy for a total of 11,521 patient care days. Fourteen critical events occurred, of which four led to increased patient care. There were eight programming errors (all involving misprogramming of the continuous infusion): three involved a family member activating the device, three were the result of an error in clinical judgment, and one involved a patient tampering with the device (one event involved more than one error). Of the four events that led to increased patient care, two involved a family member activating the device, one was the result of a programming error, and one was the result of an error in clinical judgment. All patients who experienced a critical event had an uneventful recovery. CONCLUSIONS: Following review of the critical events, it was determined that the design of the PCA device contributed to the misprogramming errors and the device was removed from service. Changes in the training of physicians and nurses were instituted to avoid recurrence of other errors identified. The incidence of serious respiratory-related critical events was 0.1%. i.v. PCA therapy has the risk of potentially serious complications and requires constant physician and nursing care with an active quality assurance program.
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BACKGROUND: Muscle rigidity frequently accompanies induction of anesthesia with opioids. The authors sought to determine whether unconsciousness and amnesia occur when humans develop rigidity and apnea after intravenous fentanyl (without other concomitant anesthetics). METHODS: The incidence and duration of rigidity and level of consciousness were evaluated and associated plasma concentrations of fentanyl were measured in 12 healthy adult male volunteers given only intravenous fentanyl. Fentanyl was infused at a rate of 150 micrograms/min until a total of 15 micrograms/kg had been administered. Arterial blood samples for fentanyl assay were drawn and responsiveness, heart rate (HR), and systolic and diastolic arterial blood pressures were determined at frequent intervals during and after infusion. If rigidity was accompanied by an Spo2 < 90%, positive pressure ventilation with 100% O2 with a mask was instituted until spontaneous ventilation resumed. RESULTS: The incidence of muscular rigidity was 50% (6/12). All subjects who developed rigidity were apneic, unresponsive, and had no recall of commands to breathe or of positive pressure ventilation. Subjects not developing rigidity remained awake and responsive. No subject developing rigidity required neuromuscular blockade to allow positive pressure ventilation and adequate oxygenation (Spo2 > 90%). When rigidity occurred, it started 3 +/- 0.9 (range 1-4) min after the peak plasma fentanyl concentration and lasted for 11.5 +/- 5.8 (range 7-23) min. Rigidity started at a plasma fentanyl concentration of 21.5 +/- 4.4 (range 16-28) ng/ml and ended at 6.9 +/- 1.5 (range 5.2-8.7) ng/ml. Baseline HR was less in the subjects who subsequently developed rigidity (56.7 +/- 7.8 vs. 67.2 +/- 7.8 P = 0.04). No differences in fentanyl plasma concentrations or predicted effect site concentrations for rigidity were detected between subjects who developed rigidity and those who did not. CONCLUSIONS: These findings support the hypothesis that unconsciousness occurs in the unstimulated subject during fentanyl-induced apnea and rigidity.