Gunshot wound injury to the genitourinary tract: a 4-year retrospective review at an academic level 1 trauma center.

Background: Firearm injuries increased significantly during the coronavirus disease 2019 (COVID-19) pandemic. We aimed to describe our experience with patients admitted to a level 1 trauma center with gunshot-related trauma to the genitourinary (GU) tract before and during COVID-19 pandemic. Methods: Patients sustaining gunshot-related trauma to the adrenals, kidneys, ureters, bladder, scrotum, testicles, penis, and urethra between January 1, 2018 and December 31, 2021 were identified from our institutional trauma database. Patient charts were queried to extract demographic information, management, and follow-up. Results: A total of 117 patients met inclusion criteria with 39 (33%) of GU injuries occurring pre-COVID, and 78 (67%) occurring during or post-COVID. Seventy-two (62%) presented with kidney injury. Patients injured in the pre-COVID period were more likely to participate in a follow-up visit by 2.17 times at 60 days (P=0.017), 1.98 times at 90 days (P=0.030), and 2.04 times at 1-year (P=0.014) than during COVID. Pre-COVID, 46% of patients were injured in the city's northwestern region and 54% from other areas, during COVID 24% of patients came from the northwestern region compared to 76% from other areas (P=0.029). Conclusions: Gunshot wounds (GSW) involving the GU tract increased during the COVID-19 pandemic, with renal injury most frequent. Follow-up visits declined by around half during the pandemic, primarily at 60 days, 90 days, and 1 year post-injury. The number of patients admitted with urologic injuries pre-COVID versus during COVID was significantly different depending on the patient's area of residence. More work is needed to evaluate the outcomes of traumatic GU injuries due to GSW pre- and post-pandemic.

Irreversible electroporation augments ß-glucan induced trained innate immunity for the treatment of pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic cancer (PC) is a challenging diagnosis that is yet to benefit from the advancements in immuno-oncologic treatments. Irreversible electroporation (IRE), a non-thermal method of tumor ablation, is used in treatment of select patients with locally-advanced unresectable PC and has potentiated the effect of certain immunotherapies. Yeast-derived particulate ß-glucan induces trained innate immunity and successfully reduces murine PC tumor burden. This study tests the hypothesis that IRE may augment ß-glucan induced trained immunity in the treatment of PC. METHODS: ß-Glucan-trained pancreatic myeloid cells were evaluated ex vivo for trained responses and antitumor function after exposure to ablated and unablated tumor-conditioned media. ß-Glucan and IRE combination therapy was tested in an orthotopic murine PC model in wild-type and Rag-/- mice. Tumor immune phenotypes were assessed by flow cytometry. Effect of oral ß-glucan in the murine pancreas was evaluated and used in combination with IRE to treat PC. The peripheral blood of patients with PC taking oral ß-glucan after IRE was evaluated by mass cytometry. RESULTS: IRE-ablated tumor cells elicited a potent trained response ex vivo and augmented antitumor functionality. In vivo, ß-glucan in combination with IRE reduced local and distant tumor burden prolonging survival in a murine orthotopic PC model. This combination augmented immune cell infiltration to the PC tumor microenvironment and potentiated the trained response from tumor-infiltrating myeloid cells. The antitumor effect of this dual therapy occurred independent of the adaptive immune response. Further, orally administered ß-glucan was identified as an alternative route to induce trained immunity in the murine pancreas and prolonged PC survival in combination with IRE. ß-Glucan in vitro treatment also induced trained immunity in peripheral blood monocytes obtained from patients with treatment-naïve PC. Finally, orally administered ß-glucan was found to significantly alter the innate cell landscape within the peripheral blood of five patients with stage III locally-advanced PC who had undergone IRE. CONCLUSIONS: These data highlight a relevant and novel application of trained immunity within the setting of surgical ablation that may stand to benefit patients with PC.

A Tumor-admixture Model to Interrogate Immune Cell-dependent Tumorigenesis.

A rigorous determination of effector contributions of tumor-infiltrating immune cells is critical for identifying targetable molecular mechanisms for the development of novel cancer immunotherapies. A tumor/immune cell-admixture model is an advantageous strategy to study tumor immunology as the fundamental methodology is relatively straightforward, while also being adaptable to scale to address increasingly complex research queries. Ultimately, this method can provide robust experimental information to complement more traditional murine models of tumor immunology. Here, we describe a tumor/macrophage-admixture model using bone marrow-derived macrophages to investigate macrophage-dependent tumorigenesis. Additionally, we provide commentary on potential branch points for optimization with other immune cells, experimental techniques, and cancer types.

Inducing trained immunity in pro-metastatic macrophages to control tumor metastasis.

Metastasis is the leading cause of cancer-related deaths and myeloid cells are critical in the metastatic microenvironment. Here, we explore the implications of reprogramming pre-metastatic niche myeloid cells by inducing trained immunity with whole beta-glucan particle (WGP). WGP-trained macrophages had increased responsiveness not only to lipopolysaccharide but also to tumor-derived factors. WGP in vivo treatment led to a trained immunity phenotype in lung interstitial macrophages, resulting in inhibition of tumor metastasis and survival prolongation in multiple mouse models of metastasis. WGP-induced trained immunity is mediated by the metabolite sphingosine-1-phosphate. Adoptive transfer of WGP-trained bone marrow-derived macrophages reduced tumor lung metastasis. Blockade of sphingosine-1-phosphate synthesis and mitochondrial fission abrogated WGP-induced trained immunity and its inhibition of lung metastases. WGP also induced trained immunity in human monocytes, resulting in antitumor activity. Our study identifies the metabolic sphingolipid-mitochondrial fission pathway for WGP-induced trained immunity and control over metastasis.

The induction of peripheral trained immunity in the pancreas incites anti-tumor activity to control pancreatic cancer progression.

Despite the remarkable success of immunotherapy in many types of cancer, pancreatic ductal adenocarcinoma has yet to benefit. Innate immune cells are critical to anti-tumor immunosurveillance and recent studies have revealed that these populations possess a form of memory, termed trained innate immunity, which occurs through transcriptomic, epigenetic, and metabolic reprograming. Here we demonstrate that yeast-derived particulate ß-glucan, an inducer of trained immunity, traffics to the pancreas, which causes a CCR2-dependent influx of monocytes/macrophages to the pancreas that display features of trained immunity. These cells can be activated upon exposure to tumor cells and tumor-derived factors, and show enhanced cytotoxicity against pancreatic tumor cells. In orthotopic models of pancreatic ductal adenocarcinoma, ß-glucan treated mice show significantly reduced tumor burden and prolonged survival, which is further enhanced when combined with immunotherapy. These findings characterize the dynamic mechanisms and localization of peripheral trained immunity and identify an application of trained immunity to cancer.

Lactate supports a metabolic-epigenetic link in macrophage polarization.

Lactate accumulation is a hallmark of solid cancers and is linked to the immune suppressive phenotypes of tumor-infiltrating immune cells. We report herein that interleukin-4 (IL-4)­induced M0 → M2 macrophage polarization is accompanied by interchangeable glucose- or lactate-dependent tricarboxylic acid (TCA) cycle metabolism that directly drives histone acetylation, M2 gene transcription, and functional immune suppression. Lactate-dependent M0 → M2 polarization requires both mitochondrial pyruvate uptake and adenosine triphosphate­citrate lyase (ACLY) enzymatic activity. Notably, exogenous acetate rescues defective M2 polarization and histone acetylation following mitochondrial pyruvate carrier 1 (MPC1) inhibition or ACLY deficiency. Lastly, M2 macrophage­dependent tumor progression is impaired by conditional macrophage ACLY deficiency, further supporting a dominant role for glucose/lactate mitochondrial metabolism and histone acetylation in driving immune evasion. This work adds to our understanding of how mitochondrial metabolism affects macrophage functional phenotypes and identifies a unique tumor microenvironment (TME)­driven metabolic-epigenetic link in M2 macrophages.

A specific low-density neutrophil population correlates with hypercoagulation and disease severity in hospitalized COVID-19 patients.

SARS coronavirus 2 (SARS-CoV-2) is a novel viral pathogen that causes a clinical disease called coronavirus disease 2019 (COVID-19). Although most COVID-19 cases are asymptomatic or involve mild upper respiratory tract symptoms, a significant number of patients develop severe or critical disease. Patients with severe COVID-19 commonly present with viral pneumonia that may progress to life-threatening acute respiratory distress syndrome (ARDS). Patients with COVID-19 are also predisposed to venous and arterial thromboses that are associated with a poorer prognosis. The present study identified the emergence of a low-density inflammatory neutrophil (LDN) population expressing intermediate levels of CD16 (CD16Int) in patients with COVID-19. These cells demonstrated proinflammatory gene signatures, activated platelets, spontaneously formed neutrophil extracellular traps, and enhanced phagocytic capacity and cytokine production. Strikingly, CD16Int neutrophils were also the major immune cells within the bronchoalveolar lavage fluid, exhibiting increased CXCR3 but loss of CD44 and CD38 expression. The percentage of circulating CD16Int LDNs was associated with D-dimer, ferritin, and systemic IL-6 and TNF-α levels and changed over time with altered disease status. Our data suggest that the CD16Int LDN subset contributes to COVID-19-associated coagulopathy, systemic inflammation, and ARDS. The frequency of that LDN subset in the circulation could serve as an adjunct clinical marker to monitor disease status and progression.

Optimizing the Combination of Immunotherapy and Trans-Arterial Locoregional Therapy for Stages B and C Hepatocellular Cancer.

Hepatocellular carcinoma (HCC), the most common primary hepatic malignancy worldwide, is the second leading cause of cancer-related death. Underlying liver dysfunction and advanced stage of disease require treatments to be optimally timed and implemented to minimize hepatic parenchymal damage while maximizing disease response and quality of life. Locoregional therapies (LRTs) such as trans-arterial chemo- and radio-embolization remain effective for intermediate liver-only and advanced HCC disease (i.e., Barcelona-Clinic liver cancer stages B and C) not amendable to primary resection or ablation. Additionally, these minimally invasive interventions have been shown to augment the immune system. This and the recent success of immune-oncologic treatments for HCC have generated interest in applying these therapies in combination with such locoregional interventions to improve patient outcomes and response rates. This report reviews the use of trans-arterial LRTs with immunotherapy for stages B and C HCC, potential biomarkers, and imaging methods for assessing the response and safety of such combinations.

Could the Induction of Trained Immunity by ß-Glucan Serve as a Defense Against COVID-19?

As the SARS-CoV-2 virus wreaks havoc on the populations, health care infrastructures and economies of nations around the world, finding ways to protect health care workers and bolster immune responses in the general population while we await an effective vaccine will be the difference between life and death for many people. Recent studies show that innate immune populations may possess a form of memory, termed Trained Immunity (TRIM), where innate immune cells undergo metabolic, mitochondrial, and epigenetic reprogramming following exposure to an initial stimulus that results in a memory phenotype of enhanced immune responses when exposed to a secondary, heterologous, stimulus. Throughout the literature, it has been shown that the induction of TRIM using such inducers as the BCG vaccine and ß-glucan can provide protection through altered immune responses against a range of viral infections. Here we hypothesize a potential role for ß-glucan in decreasing worldwide morbidity and mortality due to COVID-19, and posit several ideas as to how TRIM may actually shape the observed epidemiological phenomena related to COVID-19. We also evaluate the potential effects of ß-glucan in relation to the immune dysregulation and cytokine storm observed in COVID-19. Ultimately, we hypothesize that the use of oral ß-glucan in a prophylactic setting could be an effective way to boost immune responses and abrogate symptoms in COVID-19, though clinical trials are necessary to confirm the efficacy of this treatment and to further examine differential effects of ß-glucan's from various sources.

89Zr-Labeled Anti-PD-L1 Antibody Fragment for Evaluating In Vivo PD-L1 Levels in Melanoma Mouse Model.

The rise of programmed death-1 (PD-1)/PD-L1 immune checkpoint inhibitor therapy has been one of the most promising developments in melanoma research. However, not all the melanoma patients respond to such immune checkpoint blockade. There is a great need of biomarkers for appropriate melanoma patient selection and therapeutic efficacy monitoring. The objective of this study is to develop a novel radiolabeled anti-PD-L1 antibody fragment, as an imaging biomarker, for evaluating the in vivo PD-L1 levels in melanoma. The Df-conjugated F(ab')2 fragment of the anti-mouse PD-L1 antibody was successfully synthesized and radiolabeled with 89Zr. Both Df-F(ab')2 and 89Zr-Df-F(ab')2 maintained the nano-molar murine PD-L1 targeting specificity and affinity. 89Zr-Df-F(ab')2 showed less uptake in normal liver tissue in mice compared with its full antibody counterpart 89Zr-Df-anti-PD-L1. Positron emission tomography (PET)/computed tomography images clearly showed that 89Zr-Df-F(ab')2 possessed superior pharmacokinetics and imaging contrast over the radiolabeled full antibody, with much earlier and higher tumor uptake (5.5 times more at 2 h post injection) and much lower liver background (51% reduction at 2 h post injection). The specific and high murine PD-L1-targeting uptake at tumor foci coupled with fast clearance of 89Zr-Df-F(ab')2 highlighted its potential for in vivo PET imaging of murine PD-L1 levels and future development of radiolabeled anti-human PD-L1 fragment for potential application in melanoma patients.

Identifying Factors Predicting Prolonged Opioid Use After Mastectomy.

BACKGROUND: Women who undergo mastectomy for breast cancer may be prone to prolonged opioid use (POU). However, risk factors for long-term opioid use after mastectomy remain unclear. This study seeks to identify risk factors for POU after mastectomy. PATIENTS AND METHODS: A single-institution database was queried for women who underwent mastectomy for breast cancer between January 2016 and December 2017. Patients were stratified based on opioid use < 90 or ≥ 90 days after mastectomy or completion of their reconstruction. Clinicopathologic and operative parameters as well as preoperative and postoperative opioid usage were compared. RESULTS: Patients with opioid use ≥ 90 days after last procedure (POU) had a history of preoperative opioid use (29.3% vs 8.2%, p = 0.002), were more likely to have concomitant psychiatric illness (70% vs 35.6%, p < 0.001), and had received adjuvant chemotherapy (43.1% vs 24.7%, p = 0.03). Patients with POU also had greater daily opioid doses prescribed upon discharge (59.6 mg vs 44.6 mg, p < 0.001). On multivariable analysis, preoperative opioid use (OR 3.61, 95% CI 1.16-11.22, p = 0.03), daily oral morphine equivalents prescribed at discharge (OME-D) (OR 1.02, 95% CI 1.01-1.05, p = 0.003), and psychiatric illness (OR 4.48, 95% CI 1.85-10.89, p < 0.001) were independently associated with POU. Among opioid-naïve patients, 37% were found to have POU. Among these patients, OME at discharge (OR 1.02, 95% CI 1.003-1.04, p = 0.02) and psychiatric illness (OR 3.23, 95% CI 1.25-8.31, p = 0.02) independently predicted POU. CONCLUSIONS: Preoperative opioid use, psychiatric illness, and daily OME at discharge independently predict POU after mastectomy.

Yeast-Derived ß-Glucan in Cancer: Novel Uses of a Traditional Therapeutic.

An increased understanding of the complex mechanisms at play within the tumor microenvironment (TME) has emphasized the need for the development of strategies that target immune cells within the TME. Therapeutics that render the TME immune-reactive have a vast potential for establishing effective cancer interventions. One such intervention is ß-glucan, a natural compound with immune-stimulatory and immunomodulatory potential that has long been considered an important anti-cancer therapeutic. ß-glucan has the ability to modulate the TME both by bridging the innate and adaptive arms of the immune system and by modulating the phenotype of immune-suppressive cells to be immune-stimulatory. New roles for ß-glucan in cancer therapy are also emerging through an evolving understanding that ß-glucan is involved in a concept called trained immunity, where innate cells take on memory phenotypes. Additionally, the hollow structure of particulate ß-glucan has recently been harnessed to utilize particulate ß-glucan as a delivery vesicle. These new concepts, along with the emerging success of combinatorial approaches to cancer treatment involving ß-glucan, suggest that ß-glucan may play an essential role in future strategies to prevent and inhibit tumor growth. This review emphasizes the various characteristics of ß-glucan, with an emphasis on fungal ß-glucan, and highlights novel approaches of ß-glucan in cancer therapy.

The Role of Membrane Bound Complement Regulatory Proteins in Tumor Development and Cancer Immunotherapy.

It has long been understood that the control and surveillance of tumors within the body involves an intricate dance between the adaptive and innate immune systems. At the center of the interplay between the adaptive and innate immune response sits the complement system-an evolutionarily ancient response that aids in the destruction of microorganisms and damaged cells, including cancer cells. Membrane-bound complement regulatory proteins (mCRPs), such as CD46, CD55, and CD59, are expressed throughout the body in order to prevent over-activation of the complement system. These mCRPs act as a double-edged sword however, as they can also over-regulate the complement system to the extent that it is no longer effective at eliminating cancerous cells. Recent studies are now indicating that mCRPs may function as a biomarker of a malignant transformation in numerous cancer types, and further, are being shown to interfere with anti-tumor treatments. This highlights the critical roles that therapeutic blockade of mCRPs can play in cancer treatment. Furthermore, with the complement system having the ability to both directly and indirectly control adaptive T-cell responses, the use of a combinatorial approach of complement-related therapy along with other T-cell activating therapies becomes a logical approach to treatment. This review will highlight the biomarker-related role that mCRP expression may have in the classification of tumor phenotype and predicted response to different anti-cancer treatments in the context of an emerging understanding that complement activation within the Tumor Microenvironment (TME) is actually harmful for tumor control. We will discuss what is known about complement activation and mCRPs relating to cancer and immunotherapy, and will examine the potential for combinatorial approaches of anti-mCRP therapy with other anti-tumor therapies, especially checkpoint inhibitors such as anti PD-1 and PD-L1 monoclonal antibodies (mAbs). Overall, mCRPs play an essential role in the immune response to tumors, and understanding their role in the immune response, particularly in modulating currently used cancer therapeutics may lead to better clinical outcomes in patients with diverse cancer types.

Clinician validation of Poison Control Center (PCC) intentional exposure cases involving prescription opioids.

Poison Control Center (PCC) cases involving intentional ingestion, injection or inhalation of prescription opioids are a potentially valuable source of information on the abuse and misuse of these products. This study sought to validate PCC classifications of prescription opioid intentional exposure cases against clinical diagnostic criteria. 4,321 cases were reviewed. PCC-clinician concordance was good to excellent for Withdrawal, Abuse, and Suicide (kappa statistics: 0.73, 0.53, 0.48, respectively), but poor for Misuse and Intentional Unknown (Specific motive not known). Interrater reliability among clinicians was good (weighted kappa range: 0.56-0.68). Results demonstrate the degree of compatibility between PCC and standard nosologic classifications.

The Diversion of Ultram, Ultracet, and generic tramadol HCL.

Ultram (tramadol HCL) was approved by the Food and Drug Administration in 1994 as a non-scheduled drug under the Controlled Substance Act. The non-scheduled status was contingent on the development and implementation of a comprehensive post-marketing surveillance program by an Independent Steering Committee external to Ortho-McNeil Pharmaceutical charged with monitoring abuse and recommending scheduling if unexpectedly high abuse occurred. The program developed by this committee was composed of a variety of studies, and the results of the first three years of the surveillance efforts revealed that the rate of Ultram abuse was low. At a meeting of the FDA in 1998 to reexamine the scheduling status of Ultram, it was recommended that the scope of the postmarketing surveillance program be broadened to include data on diversion. After a 1-year pilot study, by January 2002, a nationwide diversion survey was fully operational. This brief communication describes the experiences of this diversion study, and compares the findings on the diversion of Ultram and other tramadol HCL products with that of more widely abused drugs. Survey data suggest that the diversion of Ultram and other tramadol products is low, and overall, diversion investigators did not consider tramadol to be a problem in their respective jurisdictions.

A comparison of the abuse liability of tramadol, NSAIDs, and hydrocodone in patients with chronic pain.

Concern about abuse/dependence in chronic pain patients taking opioid analgesics may lead to undertreatment of pain, yet little is known about the prevalence of abuse/dependence in these patients and how it differs among analgesic agents. The objective of this study was to assess the prevalence of tramadol abuse compared to nonsteroidal anti-inflammatory drugs (NSAIDs) and hydrocodone-containing analgesics in patients with chronic noncancer pain (CNP). The study had three arms. The first arm consisted of subjects prescribed tramadol alone; the second of subjects randomized to either NSAIDs or tramadol; and the third of subjects randomized to hydrocodone or tramadol. Each investigator received two boxes of prescriptions randomized so that one in every four prescriptions was for tramadol. Upon deciding on the therapeutically appropriate arm, the physician selected the appropriate box, opened the next envelope and completed the enclosed prescription. After the initial randomization, physicians could prescribe whatever medication was therapeutically appropriate. A total of 11,352 subjects were enrolled. Up to nine interviews using a structured questionnaire were conducted over a 12-month period. An algorithm called the "Abuse Index" was developed to identify subjects who were abusing the drug. The primary components of the index were increasing dose without physician approval, use for purposes other than intended, inability to stop its use, and withdrawal. The percent of subjects who scored positive for abuse at least once during the 12-month follow-up were 2.5% for NSAIDs, 2.7% for tramadol, and 4.9% for hydrocodone. When more than one hit on the algorithm was used as a measure of persistence, abuse rates were 0.5% for NSAIDs, 0.7% for tramadol, and 1.2% for hydrocodone. Thus, the results of this study suggest that the prevalence of abuse/dependence over a 12-month period in a CNP population that was primarily female was equivalent for tramadol and NSAIDs, with both significantly less than the rate for hydrocodone.

Rates of abuse of tramadol remain unchanged with the introduction of new branded and generic products: results of an abuse monitoring system, 1994-2004.

PURPOSE: The analgesic Tramadol HCl (Ultram) was approved in 1994 as a non-scheduled drug under the CSA provided that a novel risk-management program would be developed by an Independent Steering Committee (ISC). The risk-management program began in 1995 with the launch of Ultram, and has been modified over the past decade to accommodate Ultracet (Ultram and acetaminophen) in 2001 and generic tramadol in 2002. This provided a unique opportunity to study the potential changes in abuse as the generic and combination products became available. METHODS: To proactively detect cases of abuse and diversion, the ISC developed a comprehensive questionnaire which was completed quarterly by an extensive network of drug abuse experts (n = 309) and police agencies (n = 100) who were asked to indicate how many diversion cases involving Ultram, Ultracet, and generic tramadol were identified during the preceding 3 months and what were the ten most commonly diverted drugs in their catchment area during that period. RESULTS AND CONCLUSIONS: The data generated demonstrate that the abuse of tramadol remained very low despite new branded and generic formulations. Contrary to the hypothesis that cheaper generic drugs would lead to higher rates of abuse, we found no increase in abuse with the introduction of generic tramadol. Ultracet abuse rates, unlike those found with other widely used hydrocodone and oxycodone combination products, have been even lower than that observed for tramadol. Since the FDA has now mandated that proactive risk-management plans be implemented for new drugs, the tramadol risk-management plan may be useful as a prototypic model which can be modified to accommodate other drugs with abuse potential.

An independent assessment of MEDWatch reporting for abuse/dependence and withdrawal from Ultram (tramadol hydrochloride).

OBJECTIVE: Assess the validity of medical products reporting program (MEDWatch) reports of abuse/dependence and withdrawal associated with Ultram (tramadol). METHODS: Reports of possible abuse/dependence or withdrawal associated with Ultram during 13 quarters following launch were spontaneously reported to the manufacturer Ortho-McNeil Pharmaceutical (OMP) and also solicited from 255 NIDA grantees and addiction treatment professionals by an Independent Steering Committee (ISC). Reports were classified by the ISC using DSM-IV criteria, by the Drug Safety and Surveillance (DSS) units of Robert Wood Johnson Pharmaceutical Research Institute (PRI) using World Health Organization Adverse Reaction Terms (WHOART) terms, and reported to the food and drug administration (FDA) via MEDWatch. Rates of abuse/dependence and withdrawal per 100000 persons exposed were calculated separately for classifications made by the PRI and the ISC, and confidence intervals calculated to determine the degree to which they agreed. RESULTS: For 681 reports submitted to PRI, confidence intervals of ISC ratings contained PRI ratings 12 of 13 times for abuse/dependence, and 12 of 13 times for withdrawal. For 242 reports submitted to the ISC, confidence intervals of ISC ratings contained PRI ratings 10 of 13 times for abuse/dependence, and 12 of 13 times for withdrawal. Proactive surveillance increased the total number of cases of abuse/dependence but not withdrawal. Many cases of withdrawal without signs or symptoms of abuse/dependence were identified. CONCLUSIONS: There was good/excellent concordance between MEDWatch and ISC classifications. Proactive surveillance increased cases of abuse/dependence but not withdrawal. Withdrawal with no signs or symptoms of dependence was common. More use of proactive surveillance is likely to improve assessments of public health risks associated with adverse events.