Xiulu Ruan

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

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...

Comment on Deckert et al.: A systematic review of the outcomes reported in multimodal pain therapy for chronic pain.

We read with interest the article by Deckert and colleagues (Deckert et al., 2016), entitled ‘A systematic review of the outcomes reported in multimodal pain therapy for chronic pain’, published in the European Journal Pain. The authors state that there are no recommendations provided for the outcome domains of chronic pain. Their aim was to summarize all reported outcome domains in studies assessing the effects of multimodal pain therapy (MPT) for chronic pain, and to subsequently generate a consensusbased construct of a core outcome set of domains in the field of chronic pain management. They selected 70 studies out of 3626 relevant titles. The authors found that there was great variation in the specific domains chosen to address these core health areas and no outcome domain was measured consistently in all studies. They conclude that the current lack of standardization of outcome domains in MPT studies hinders with regard to readily comparing interventions from different trials and is a barrier towards evidence-based decision making. Based on these results, the development of a core outcome set of domains for MPT is needed and has been initiated (Deckert et al., 2016). We want to point out that MPT programmes, referred to as interdisciplinary, multidisciplinary or comprehensive programmes in the United States have been in existence for over half a century (Meldrum, 2007). While perhaps initially an American phenomenon, interdisciplinary chronic pain management programmes have certainly thrived in other areas of the world. In 1999, it was estimated that there were over 1000 interdisciplinary pain management programmes in the United States (Schatman, 2012). Unfortunately, this number has dropped dramatically, with the number of programmes currently operating estimated at 150 (Jeffery et al., 2011). The Institute of Medicine estimates that there are approximately 100 million Americans that suffer from chronic pain (Dzau and Pizzo, 2014). These data suggest that there is approximately one interdisciplinary programme for every 670,000 chronic pain patients in the United States. The root of the problem is neither in clinical research nor in clinical practice model. European, as well as American leaders, both promote guidelines for chronic pain states such as non-specific low back pain, involving a broad multidisciplinary assessment for persistent pain of 6 weeks or greater to determine a role for a multiand interdisciplinary pain therapy programme (Casser et al., 2013; Pergolizzi et al., 2013). They indicate that they believe the ‘complexity of the pain experience’ means that the diverse aspects of chronic pain are best treated by a multidisciplinary team, enabling patients to benefit from the co-ordination and integration of various medical disciplines and treatment modalities. They are more likely to benefit from an early and accurate diagnosis, and to receive various therapies specifically tailored to their individual needs.’ (Pergolizzi et al., 2013). In this regard, in Belgium for example, nine multidisciplinary centres for treating chronic pain were established in 2005. Each included at least three medical and three paramedical specialties, and the Director had to have both extra training and at least 3-year full-time experience in pain management. The success of these centres led to the creation of 36 new multidisciplinary teams to treat patients with early stage pain, employing a biopsychosocial approach and including in addition to hospital-related services, a pain specialist and a psychiatrist. Furthermore, 73 different locations were created to address pain as early as possible, with trained nurses to identify patients at risk of developing chronic pain and referring them to a pain specialist as needed (Onkelinx, 2010). Since 2013, this model has been further adapted and extended to 35 multidisciplinary pain clinics and to multidisciplinary pain teams in all Belgian hospitals (n = 104). Additionally, 13 specialized centres for paediatric pain were recognized (SPF Sant e publique, S ecurit e de la Châıne alimentaire et Environnement, 2016).

Defining Chronic Pain

To the Editor: We read with interest the article by Taylor, et al , “Is Chronic Pain a Disease in Its Own Right? Discussions from a Pre-OMERACT 2014 Workshop on Chronic Pain,” published in The Journal of Rheumatology 1. First, we are quite amazed to see how widespread the attendees’ responses were regarding the definition of chronic pain (CP) after a few presentations were given, including 1 proposing that CP should no longer be seen as a symptom. Out of the 5 choices given for the definition of CP, 9% selected “disease,” 26% selected “condition,” 11% selected “syndrome,” 23% selected “symptom complex,” and 31% selected “none of the above.” It is somewhat difficult to accept that only 9% of attendees chose “disease” during the pre-work survey at the workshop, where “Is chronic pain a disease in its own right?” was supposed to be the main objective of this meeting. … Address correspondence to Associate Professor X. Ruan, Anesthesiology, Louisiana State University Health Science Center, 1542 Tulane Ave., New Orleans, Louisiana 70112, USA. E-mail: drxruan88{at}gmail.com

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.

Comment on Roughan et al.: Meloxicam prevents COX‐2‐mediated post‐surgical inflammation but not pain following laparotomy in mice

We read with great interest the article by Roughan et al. (2015), entitled ‘Meloxicam prevents COX-2mediated post-surgical inflammation but not pain following laparotomy in mice’, published in European Journal of Pain. Since inflammation is considered a major contributor to post-surgical pain, non-steroidal anti-inflammatory drugs (NSAIDs) are commonly utilized as analgesics. However, it is considerably unclear how successful NSAIDs are as analgesics in mice. The investigation evaluated the post-surgical anti-inflammatory and analgesic effects of meloxicam in mice. The study found that meloxicam at 5 and 20 mg/kg significantly reduced abdominal inflammation; however, all other parameters indicated pain or another negatively affective state remained. Roughan et al. attribute the finding to a range of factors, including, but not limited to inflammation (Roughan et al., 2015). The authors are puzzled by their finding and the notion that a causal relationship between inflammation and pain generally holds true, although in their study, they found pain continued despite effective COX-2 inhibition by large doses of meloxicam. However, we wonder if the lack of antinociception observed was actually related to the inactivation of endogenous opioid system because of meloxicam. In a recent review article, Stein (2013) states that peripheral opioid receptors are expressed in peripheral sensory (dorsal root ganglion) neurons and can interact with exogenous or endogenous opioid ligands, both in animals and in humans. Inflammation of peripheral tissue leads to up-regulation of such opioid receptors and to local production of endogenous opioid peptides in immune cells. Opioid receptors in the periphery can be a site for mediating analgesia (Stein et al., 1989; Hassan et al., 1993; Vadivelu et al., 2011). Peripheral analgesic effects of opioids are enhanced under inflammatory conditions and tissue injury (Sch€afer, 1999; Stein et al., 2001). Furthermore, inflammation increases the peripherally directed axonal transport of opioid receptors, which leads to up-regulation of opioid receptors on peripheral nerve terminals (Stein et al., 2001). In addition, the number of primary afferent neuron terminals is increased in inflamed tissues (Hassan et al., 1993). Therefore, inflammation is needed for the activation of the peripheral opioid system. We speculate, therefore, that there needs to be a balance between peripheral tissue inflammation, which causes nociception, but as well, stimulates the activation of the endogenous peripheral opioid system. When large dose of an NSAID is used, it suppresses the needed tissue inflammation and thus, the endogenous opioid system. We wonder if, by lowering the dosage of meloxicam, a balance is achieved with controlled inflammation (not completely suppressed inflammation) and the activation of the endogenous peripheral opioid system such that an overall analgesic effect could be obtained. Therefore, we suggest the authors to lower the dose of meloxicam from 5 mg or 20 mg/kg to perhaps 0.5 mg or 2.5 mg/kg in their model, especially considering the fact that clinically, physicians routinely use 15 mg or 30 mg daily in a 60 kg person for control of inflammation and pain. In summary, we applaud the authors for their investigation; however, we think that the dosages of 5 mg or 20 mg/kg may be too high.

Intractable pruritus during outpatient epidural hydromorphone infusion: a case report and a focused review of the literature.

BACKGROUND Intraspinal drug delivery therapy has been increasingly used in patients with intractable, nonmalignant pain who have failed to respond to conventional treatment or cannot tolerate systemic opioid(s) due to adverse events. By infusing a small dose of an opioid analgesic directly into the cerebrospinal fluid, near opioid receptors, profound spinal analgesia can be obtained. Before the implantation of permanent intraspinal pump, a neuraxial opioid infusion trial is usually conducted to demonstrate the effectiveness of neuraxial opioid for analgesia. Patient-controlled epidural opioid infusion trial, performed in an outpatient setting, is one of the approaches used to conduct such a trial. OBJECTIVE To report a case of severe pruritus observed during the continuous epidural hydromorphone infusion trial and to conduct a focused review of the literature. CASE REPORT An otherwise healthy 56-year-old lady, with a 4-year history of severe low back pain and bilateral leg pain due to failed back surgery syndrome, was referred to our clinic for intraspinal drug delivery therapy. Following a preimplantation psychological evaluation confirming her candidacy, she consented to an outpatient patient-controlled continuous epidural hydromorphone trial. A tunneled lumbar epidural catheter was placed at L3-L4 with catheter tip advanced to L2 under fluoroscopic guidance. Satisfactory catheter placement was confirmed by epidurogram. The catheter was then tunneled subcutaneously and connected to a Microject™ patient-controlled epidural analgesia (PCEA) pump (Codman, Raynham, MA). The pump was programmed to deliver hydromorphone 0.3 mL/h (0.06 mg, concentration 0.2 mg/mL) at basal rate of 0.3 mL/h, with bolus dose set at 0.2 mL (0.04 mg) and 30-minute lockout interval. The patient was instructed how to operate the infusion pump prior to discharging home. During the infusion trial, she reported satisfactory analgesia (>90 percent pain reduction) and was able to reduce her oral opioid dose by more than 80 percent. However, she developed severe, persistent itching, unresponsive to meticulous epidural infusion titration or various antipruritic treatments. Her pruritus remained severe and unabated until a few hours after the termination of the epidural hydromorphone infusion. CONCLUSION Pruritus may occur and persist during epidural hydromorphone infusion. This report describes severe pruritus in a patient on epidural hydromorphone administration, in the setting of an outpatient infusion trial.

Discordant reporting of nonmedical opioid use

We read with interest the article by Palamar and colleagues (1), published in The American Journal of Drug and Alcohol Abuse. The authors aimed to study the prevalence and correlates of discordant self-reporting of nonmedical use of opioids in a national sample. They utilized a nationally representative sample of 31,149 American high school seniors in the Monitoring the Future study (2009–2013), and discordant responses between self-reported 12-month nonmedical opioid use and self-reported 12-month nonmedical Vicodin and OxyContin use (reporting Vicodin/OxyContin use, but not reporting “opioid” use) were assessed. The authors found that 37.1% of those reporting nonmedical Vicodin use and 28.2% of those reporting nonmedical OxyContin use did not report overall nonmedical opioid use. Prevalence of nonmedical opioid use (8.3%) would increase when factoring in Vicodin, OxyContin, or both, by 2.8%, 1.3%, and 3.3%, respectively. Palamar et al. have concluded that the relevance of nonmedical opioid use may be underreported, particularly among specific subpopulations (1). Palamar et al. stated “According to the National Survey on Drug Use and Health (NSDUH), Vicodin appears to be the most prevalent opioid used in a nonmedical manner in the US, used by an estimated 14.2% of adults aged 18–25 in 2013 (Ref. 8).” Interestingly and surprisingly, we could not find, even once, the word “Vicodin” in the cited reference. Nor could we find words like “Norco,” “Lortab,” or “hydrocodone” in the cited reference. We wonder where the statement “Vicodin appears to be the most prevalent opioid used in a nonmedical manner in the US, used by an estimated 14.2% of adults aged 18–25 in 2013” originated from? McCabe et al. (2) found that, in high school seniors in the US, an estimated 80% of nonmedical users had an earlier history of medical use and had obtained opioids from a prescription written by their medical providers. They also found that odds of substance use behaviors were greater among individuals who reported any history of nonmedical use of prescription opioids relative to those who reported medical use only. Palamar et al. used multivariable logistic regression to determine the characteristics of students who were most likely to provide a discordant response (1). Characteristics such as age, sex, race, and religiosity, etc., were weighted in the study. However, we wonder whether earlier history of medical use of opioids should have been weighted as well in their study? Young et al. (3) conducted a survey in 2579 7th–12th grade students to study nonmedical use of prescription medications by identifying distinguishing characteristics of two subtypes of adolescent nonmedical users of prescription opioids. The authors found that sensationseeking nonmedical users were best characterized by rule breaking and aggressive behaviors and possible substance dependence. Medical users and nonmedical self-treating users were best characterized by somatic complaints, anxiety/depressive symptoms, and history of sexual victimization (3). Young et al. found that approximately 14% (n = 373) of the sample reported medical use of prescription opioids in the past 12 months, while 5% (n = 148) of the sample reported nonmedical use of prescription opioids in the past 12 months. The most common reason for nonmedical use was “to relieve pain” (n = 91, 62.8%), followed by “to get high” (n = 23, 15.9%) and “to experiment” (n = 16, 11.0%) (3). To this end, we wonder what percentage of the students reported in the study of Pamalar et al. were actually using prescription opioids, including Oxycontin and Vicodin for underlying pain? Last, Palamar et al. cited their earlier work showing that frequent nonmedical opioid use is associated with increased risk for heroin initiation (4). However, Compton and colleagues (5) recently published a review article in the NEJM, pointing out that only a small fraction of nonmedical prescription opioid users initiate heroin use. Compton et al. conclude that the available data suggest that the nonmedical use of prescription opioid is neither necessary nor sufficient for the initiation of heroin