Srinivas Chiravuri

A Multidrug Delivery System Using a Piezoelectrically Actuated Silicon Valve Manifold With Embedded Sensors

This paper describes a drug delivery system for chronic pain that can accommodate multidrug protocols. An element that is important to the function of the system is a customized silicon micromachined valve manifold. Each valve is piezoelectrically actuated and operates by pressing an elongated valve seat against a shared glass substrate. The dual-valve substrate has two inlets and one outlet; a piezoresistive pressure sensor is embedded in the Si structure near each of these three ports. The sensors, which permit closed-loop control and error monitoring of the flow rate, have a typical sensitivity of 698 ppm/kPa. The 1 × 1.5 × 3 cm3 manifold provides modulation and mixing capabilities. The manifold is integrated into a stainless steel housing with a total volume of 130 cm3 and a reservoir volume of 40 cm3. Two spring-loaded polyethylene reservoirs feed the valve manifold at pressures up to 0.52 kPa/mL. Benchtop tests of bolus and continuous flow delivery demonstrate flow rates ranging from 2.30 to 0.51 mL/h. (Both larger and smaller rates can be achieved by adjusting the parameters of the manifold valves or reservoir springs.) Additional tests suggest that the system can compensate for changes in spinal fluid pressure and that pressure profiles can be used to detect catheter occlusions and disconnects.

Comparing fatal cases involving U-47700.

U-47700 (3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]N-methylbenzamide) is a novel compound with opioid properties, developed by Upjohn in the 1970s and derived from the earlier opioid analgesic AH-7921 (3,4-dichloro-N{[1-(dimethylamino)-cyclohexyl]methyl}benzamide) [1]. U-47700 is a structural isomer of AH-7921 [2]. AH-7921, which possesses the same potency as morphine, was first identified in 2012 in a seizure purchased over the internet and recently entered the recreational and illicit drug market as new psychotropic substance in Japan, the USA, and Europe [3]. U-47700 was never studied in humans and is not registered for medical use in humans. Very little, if any, information on it is available in scientific literature [2, 4]. Since the substance is not scheduled or controlled, it is openly sold on the internet as an opioid ‘legal high’. Anecdotal evidence from user reports on specialized internet drug fora reveals that U-47700 is actively being used as a legal substitute for other strong opioids, such as morphine, heroin, or even fentanyl [3]. U-47700 is only controlled in Finland and Sweden (the latter since 1/26/ 2016). U-47700 is approximately 7.5 times more potent than morphine [3]. Interestingly and surprisingly, there are only two fatal case reports in the literature [2, 3] involving U-47700. Remarkably, both cases involved young adult males, one is a 30-year-old, the other is a 27-year-old; one in Belgium (Case A), the other in UK (Case B). Authors of both papers claimed their case to be the ‘‘first’’ fatality case involving U-47700, which is understandable, as not only both incidents happened roughly at the same time, i.e., January, 2016, but both reports were published roughly at the same time, i.e., May, 2016. A PubMed search using ‘‘U-47700’’ returned only two entries, i.e., the reports by Coopman et al. and Elliott et al. We would like to compare and comment on these two reports. In Case A, published in Forensic Science International, Coopman and colleagues [3] describe a 30-year-old man, found dead in his home after inhaling fumes of a powder burned on aluminum foil. Blood and urine were taken by the medical examiner during the external body examination and submitted to the laboratory for a comprehensive systematic toxicological analysis. A toxic fentanyl level of 10.9 lg/L was measured from a subclavian blood sample. A powder found in the victims’ home was transferred to the laboratory for analysis, in which trace amounts of fentanyl (0.0035 %, m/m) and U-47700 (0.0012 %, m/m) were identified by gas chromatography mass spectrometry. The blood and urine U-47700 concentrations were 13.8 and 71.0 lg/L, respectively. Coopman and colleagues report that based on circumstantial evidence (police investigation, crime scene) and the results of the toxicological analysis, the medical examiner concluded that the cause of death was an acute intoxication and overdose with fentanyl and U-47700, ‘‘immediately after inhaling the fumes of the vaporized powder.’’ It was presumed the death was & Xiulu Ruan drxruan88@gmail.com

Compact, power-efficient architectures using microvalves and microsensors, for intrathecal, insulin, and other drug delivery systems☆

This paper describes a valve-regulated architecture, for intrathecal, insulin and other drug delivery systems, that offers high performance and volume efficiency through the use of micromachined components. Multi-drug protocols can be accommodated by using a valve manifold to modulate and mix drug flows from individual reservoirs. A piezoelectrically-actuated silicon microvalve with embedded pressure sensors is used to regulate dosing by throttling flow from a mechanically-pressurized reservoir. A preliminary prototype system is demonstrated with two reservoirs, pressure sensors, and a control circuit board within a 130cm(3) metal casing. Different control modes of the programmable system have been evaluated to mimic clinical applications. Bolus and continuous flow deliveries have been demonstrated. A wide range of delivery rates can be achieved by adjusting the parameters of the manifold valves or reservoir springs. The capability to compensate for changes in delivery pressure has been experimentally verified. The pressure profiles can also be used to detect catheter occlusions and disconnects. The benefits of this architecture compared with alternative options are reviewed.

Dual drug delivery device for chronic pain management using micromachined elastic metal structures and silicon microvalves

This paper describes a dual-chamber drug delivery microsystem that provides regulated flow from two spring- pressurized balloon reservoirs using independent microvalves. A preliminary prototype has been constructed with the primary components. Micromachined bulk metal springs (Co-Ni-Cr alloy), with an in-plane spring constant exceeding 300 N/m, are used in conjunction with 18.8 mL reservoirs, and provide 15 kPA pressure when the balloons are fully inflated. A piezoresistive pressure sensor that is embedded in the microvalves monitors reservoir pressure with a sensitivity of 250 ppm/kPa, and is used to regulate bolus delivery. Two control plans for the valve and their respective limitations are presented. In a demonstration of regulated bolus delivery, 1.5 mL bolus doses are delivered at different rates.

Recurrent Cellulitis Associated with Long-Term Intrathecal Opioid Infusion Therapy: A Case Report and Review of the Literature

BACKGROUND Lower-limb edema is recognized as an untoward side effect of intrathecal opioid therapy. Cellulitis, an acute, spreading pyogenic inflammation of the dermis and subcutaneous tissue, predisposed by persistent leg edema, can become problematic in patients on intraspinal opioid infusion therapy. OBJECTIVE To present a case of recurrent cellulitis in an elderly lady with persistent leg edema associated with intrathecal morphine/hydromorphone infusion therapy. CASE REPORT Sixty-one-year-old woman with intractable chronic low back pain and bilateral leg pain treated with an intrathecal infusion of morphine up to 5 mg/day over 3 months with satisfactory pain control developed progressive lower extremity edema, complicated by recurrent cellulitis, requiring repeated hospitalization and intravenous antibiotic treatment. Switching to intrathecal hydromorphone helped minimally. Intrathecal baclofen and clonidine infusion resulted in complete resolution of leg edema and pain relief over the following 12 months. CONCLUSION Intrathecal Baclofen and Clonidine may be used as alternatives to provide spinally mediated antinociception when intraspinal opioid fails due to pharmacological side effects such as persistent edema.

Toxicological testing when evaluating fatal cases suspected of acute fentanyl toxicity

Fentanyl, a structural relative of the reverse ester of meperidine, is a second generation synthetic phenylpiperidine synthesized and introduced into clinical anesthesia practice as fentanyl citrate in 1968 [1]. Fentanyl-mediated or modulated responses involve action at the l-opioid receptor as an agonist at the dorsal horn inhibiting ascending pain pathways in the rostral ventral medulla, increasing pain threshold, and producing both analgesic and sedative effects. Related to its low molecular weight, lipophilic nature, high potency, and short duration of action, fentanyl has been developed with several unique methods of delivery, including transmucosal and transdermal delivery. Development of the transdermal delivery system in 1990 was considered the primary reason for the 1100 % increase in fentanyl prescription rate observed from 1990 to 1996 [2]. The Federal Drug Administration approved a generic version in 2005. The transdermal system is a favorable mode of administration and bioavailability of close to 98 %. There are two types of transdermal patches, the reservoir and the matrix system. The reservoir patch contains a fentanyl-based gel with hydroxyethyl cellulose; the delivery is determined by a rate-controlling membrane between the drug reservoir and the skin. The matrix patch contains fentanyl in the polyacrylate adhesive matrix itself and the drug is released continuously into the skin [3]. The rate of delivery is dependent on the surface area of the patch. The reservoir patch is currently being phased out in favor of the matrix system because the matrix formulation decreases the risk of accidental overdose and drug leakage and is also smaller and thinner (Margetts et al.). Expanded utilization led to the total number of prescriptions written for generic and brand name transdermal fentanyl being 4.3 million by 2005 [4]. It has been suggested that many fentanyl related deaths are due to the increased potency of fentanyl compared to other abused opioids. Fentanyl is approximately 80–100 times more potent than morphine on a weight per weight basis [5]. However, deaths in which fentanyl is detected challenge medical examiners who must determine whether a given case represents therapeutic administration or overdose. Postmortem blood fentanyl concentrations of 3–383 ng/mL have been reported in deaths attributed solely to fentanyl, while concentrations of 2–152 ng/mL were observed in mixed fentanyl overdose deaths [6]. Deaths deemed natural or with fentanyl reported as an incidental finding had postmortem blood fentanyl concentrations ranging from 2.7 to 33 ng/mL [7]. This significant overlap between the etiology of death categories demonstrates the difficulty in interpreting postmortem blood fentanyl concentrations, leading to the conclusion that postmortem blood fentanyl concentrations are not representative of antemortem concentrations [6]. This opinion was concurred by Gill et al. [8], who previously stated that the very wide and overlapping ranges of postmortem fentanyl concentrations & Xiulu Ruan drxruan88@gmail.com

Using postmortem blood and urine norfentanyl/fentanyl ratios in the investigation of fentanyl-related deaths

Sir,Deaths in which fentanyl is detected challenge medical examiners, who must decide whether a given death represents therapeutic administration or was an overdose.[1] Numerous independent studies...

The effect of bench model fidelity on fluoroscopy-guided transforaminal epidural injection training: a randomized control study.

Background and Objectives The purpose of this study was to determine whether high-fidelity simulators provide greater benefit than low-fidelity models in training fluoroscopy-guided transforaminal epidural injection. Methods This educational study was a single-center, prospective, randomized 3-arm pretest-posttest design with a control arm. Eighteen anesthesia and physical medicine and rehabilitation residents were instructed how to perform a fluoroscopy-guided transforaminal epidural injection and assessed by experts on a reusable injectable phantom cadaver. The high- and low-fidelity groups received 30 minutes of supervised hands-on practice according to group assignment, and the control group received 30 minutes of didactic instruction from an expert. Results We found no differences at posttest between the high- and low-fidelity groups on global ratings of performance (P = 0.17) or checklist scores (P = 0.81). Participants who received either form of hands-on training significantly outperformed the control group on both the global rating of performance (control vs low-fidelity, P = 0.0048; control vs high-fidelity, P = 0.0047) and the checklist (control vs low-fidelity, P = 0.0047; control vs high-fidelity, P = 0.0047). Conclusions Training an epidural procedure using a low-fidelity model may be equally effective as training on a high-fidelity model. These results are consistent with previous research on a variety of interventional procedures and further demonstrate the potential impact of simple, low-fidelity training models.

Increased Risk of Depression Recurrence After Initiation of Prescription Opioids in Noncancer Pain Patients

To the Editor: We read with interest the article by Scherrer and colleagues published in The Journal of Pain. The authors conducted a retrospective study using data from Veterans Health Administration (VA; n = 5,400), and Baylor Scott & White Health (n = 842). They reported that patients exposed to an opioid compared with those unexposed had a significantly greater risk of depression recurrence in both patient populations. They conclude that their results suggest opioid use doubles the risk of depression recurrence even after controlling for pain, psychiatric disorders, and opioid misuse. In general, retrospective epidemiological studies using electronic medical record data suffer tremendously from the confounder of inaccurate or inappropriate diagnostic coding for the predictor of interest or the outcome of interest. In the methodology section, Scherrer et al described ‘‘Patients were defined as having depression if they had 2 or more visits in the same 12-month period and/or 1 hospital discharge diagnosis with an ICD-9-CM code for depression (ie, 296.2, 296.3, and 311).’’ We question the accuracy and validity of using International Classification of Diseases, Ninth Revision, Clinical Modification code for depression (ie, 296.2, 296.3, and 311), considering the code 311 actually represents a mental state of depressed mood characterized by feelings of sadness, despair and discouragement, not considered clinical depression. Thus, although the use of code 311 may identify people who are at risk for meeting criteria for major depression in the future or recent past and who have significant depressive symptoms, the use of this code means that the ‘‘depressed’’ subgroup includes some individuals who may not, in fact, be depressed. Therefore, this issue plagues the report and leads to an overestimation of effect size reported in the study. Recently, the US Government Accounting Office conducted a review, in which a sample of 30 veterans’ medical recordswere selected. Itwas found thatmost of them

Fentanyl–Norfentanyl Concentrations During Transdermal Patch Application: LC–MS-MS Urine Analysis

We read with interest the article by Cummings et al. (1), entitled “Fentanyl–Norfentanyl Concentrations During Transdermal Patch Application: LC–MS-MS Urine Analysis”, published in the Journal of Analytical Toxicology. The authors compared the present investigation, a much larger population of patients using therapeutic fentanyl patches, with a previous study by Poklis and Backer (2), in order to determine whether the prior study was accurate in predicting the range and median levels of fentanyl and norfentanyl concentrations, a decade later. The authors aimed at transforming their data to develop a model, as to provide a historical picture of expected patient values for fentanyl. Cummings et al. believe that the resultant near Gaussian distribution data, which is dose independent, should be of value to physicians in quickly assessing whether their patients are consistent with the historical population in the broad terms of their model (1). We would like to commend Cummings et al. for their insightful and explorative research effort. We believe that the authors’ work may have far reaching clinical and pragmatic impact. The use of transdermal fentanyl systems has increased over recent years, especially in patients with chronic pain (3). There has been a substantially increased fentanyl prescribing and associated fentanyl mortality, as a result of increased accessibility of fentanyl (4, 5). With the increase in fentanyl patch prescriptions for therapeutic reasons, it is likely that misuse cases will become more relevant. Thus, patient selection and therapeutic monitoring are critical in patients who are prescribed potent opioids, such as fentanyl patches. Urine drug testing can provide valuable information about patients’ compliance with their pharmaceutic regimen, especially in documenting opioid tolerance level, which therefore can be vitally important in impairment or overdose cases. Fatalities involving fentanyl often challenge medical examiners who must determine whether a given case represents therapeutic administration or overdose. We believe that this is especially true when fentanyl is involved along with other drugs, i.e., when one needs to find out, with some degree of certainty, whether acute fentanyl toxicity did occur and caused the death of the patient. There is a very wide and overlapping range of postmortem fentanyl concentrations that effectively nullify the utility of correlating the dose and expected postmortem concentration for any particular death (6). We recommend obtaining both a blood fentanyl-to-norfentanyl ratio and urine fentanyl-to-norfentanyl ratio when fentanyl toxicity is suspected (7). Together, these data may provide valuable information on the rapidity of death and fentanyl tolerance status at death, which may help to clarify the role fentanyl played in the decedent’s death. Thus, the concentrations of urine norfentanyl and fentanyl as well as their ratio obtained under routine therapeutic condition may become particularly valuable, in case of an accidental overdose involving fentanyl along with other drugs. By comparing the urine concentrations of norfentanyl and fentanyl as well as the ratio with that obtained under routine therapeutic condition, one may be able to estimate the status of abstinence at the time of the accident (7). In a previous study, Poklis and Backer (2) demonstrated the wide variation in concentrations of fentanyl and norfentanyl in random urine specimens following application of transdermal fentanyl patches. The authors concluded: “In general, one may expect to find urine norfentanyl concentrations three to four times higher than those of fentanyl” (2). However, we notice that in the current study, the concentrations of norfentanyl are roughly five to six times higher than that of fentanyl. We are surprised to see that Cummings et al. did not comment on this difference. As a matter of fact, the ratio of urinary norfentanyl to fentanyl was never mentioned throughout the current study. We think thus that this is a very critical omitted point and an important opportunity which was missed in this investigation.