Case Series: Limited Opioid Withdrawal With Use of Transdermal Buprenorphine to Bridge to Sublingual Buprenorphine in Hospitalized Patients.

BACKGROUND: Prerequisite opioid withdrawal symptoms prior to buprenorphine induction are unacceptable to many patients. We assessed whether transdermal buprenorphine minimized withdrawal while bridging to sublingual therapy among hospital inpatients. METHODS: Retrospective chart review of (n = 23) inpatients with opioid use disorder or opioid dependence due to chronic pain. RESULTS: Of 23 inpatients, 65% transitioned without symptoms, while 35% experienced mild withdrawal. Ninety-six percent completed planned hospitalizations, with 83% engaged in treatment 4 weeks post-discharge. DISCUSSION AND CONCLUSIONS: Bridging to sublingual therapy with transdermal buprenorphine patches was feasible without withdrawal symptoms. SCIENTIFIC SIGNIFICANCE: This strategy may facilitate buprenorphine therapy in hospital inpatients. (Am J Addict 2019;00:1-4).

Perioperative Pain and Addiction Interdisciplinary Network (PAIN) clinical practice advisory for perioperative management of buprenorphine: results of a modified Delphi process.

Until recently, the belief that adequate pain management was not achievable while patients remained on buprenorphine was the impetus for the perioperative discontinuation of buprenorphine. We aimed to use an expert consensus Delphi-based survey technique to 1) specify the need for perioperative guidelines in this context and 2) offer a set of recommendations for the perioperative management of these patients. The major recommendation of this practice advisory is to continue buprenorphine therapy in the perioperative period. It is rarely appropriate to reduce the buprenorphine dose irrespective of indication or formulation. If analgesia is inadequate after optimisation of adjunct analgesic therapies, we recommend initiating a full mu agonist while continuing buprenorphine at some dose. The panel believes that before operation, physicians must distinguish between buprenorphine use for chronic pain (weaning/conversion from long-term high-dose opioids) and opioid use disorder (OUD) as the primary indication for buprenorphine therapy. Patients should ideally be discharged on buprenorphine, although not necessarily at their preoperative dose. Depending on analgesic requirements, they may be discharged on a full mu agonist. Overall, long-term buprenorphine treatment retention and harm reduction must be considered during the perioperative period when OUD is a primary diagnosis. The authors recognise that inter-patient variability will require some individualisation of clinical practice advisories. Clinical practice advisories are largely based on lower classes of evidence (level 4, level 5). Further research is required in order to implement meaningful changes in practitioner behaviour for this patient group.

The perioperative patient on buprenorphine: a systematic review of perioperative management strategies and patient outcomes.

BACKGROUND: An increasing number of patients with opioid use disorder (OUD) are treated with opioid agonist-antagonists such as buprenorphine/naloxone. Perioperative management of patients on buprenorphine/naloxone is inconsistent and remains a controversial topic with mismanagement posing a significant risk to the long-term health of these patients. METHODS: We performed a systematic literature search involving Medline, Medline In-Process, Embase, Cochrane Central, Cochrane Database of Systematic Reviews, PsycINFO, Web of Science (Clarivate), Scopus (Elsevier), CINAHL (EbscoHosst), and PubMed (NLM). RESULTS: Eighteen studies were included in the final sample, including one controlled study and four observational studies . Neither the controlled study nor the observational studies assessed addiction treatment retention, harm reduction, or long-term mortality rates as primary or secondary outcomes. Of the observational studies, authors showed equivalent peri- and postoperative pain control among buprenorphine continued patients. All but one authors described adequate analgesia among the case reports in which buprenorphine ≤ 16 mg sublingually (SL) daily was continued during the perioperative period. Long-term harm reduction was not reported with only three case reports including any long-term abstinence or relapse rates. CONCLUSIONS: The current understanding of the risks and benefits of continuing or stopping buprenorphine perioperatively is limited by a lack of high-quality evidence. Observational studies and case reports indicate no evidence against continuing buprenorphine perioperatively, especially when the dose is < 16 mg SL daily. In patients with significant potential for relapse, such as those with a recent history of OUD, the discontinuation of buprenorphine should have a strong rationale supported by patient and surgical preferences. Future studies require standardized reporting of median doses, details on the route of delivery, dosing schedules and any dosing changes, and rates of addiction relapse, including long-term morbidity and mortality where possible.

RéSUMé: CONTEXTE: Un nombre croissant de patients présentant un trouble d'utilisation des opioïdes (TUO) sont traités avec des agonistes/antagonistes des opioïdes, tels que la buprénorphine et la naloxone. La gestion périopératoire des patients sous buprénorphine/naloxone n'est pas constante et reste un sujet de controverses; de plus une mauvaise gestion pose un risque significatif pour la santé à long terme de ces patients. MéTHODES: Nous avons effectué une recherche systématique de la littérature dans les bases de données suivantes : Medline, Medline In-Process, Embase, Cochrane Central, Cochrane Database of Systematic Reviews, PsycINFO, Web of Science (Clarivate), Scopus (Elsevier), CINAHL (EbscoHosst) et PubMed (NLM). RéSULTATS: Dix-huit études ont été incluses dans l'échantillon final, y compris une étude contrôlée et quatre études observationnelles. Ni l'étude contrôlée ni les études observationnelles n'ont évalué la continuation du traitement de l'addiction, la réduction des préjudices infligés ou les taux de mortalité à long terme parmi les critères d'évaluation principaux ou secondaires. Dans les études observationnelles, les auteurs ont montré qu'il y avait un contrôle équivalent de la douleur en péri- et postopératoire chez les patients continuant à recevoir de la buprénorphine. Tous les auteurs sauf un ont décrit une analgésie satisfaisante dans les rapports de cas où la buprénorphine sublinguale avec une dose ≤ 16 mg par jour était maintenue pendant la période périopératoire. La réduction des préjudices à long terme n'était pas décrite; seulement trois rapports de cas indiquaient le taux d'abstinence à long terme ou les taux de rechute. CONCLUSIONS: Les connaissances actuelles des risques et avantages de la poursuite ou de l'arrêt de la buprénorphine en période périopératoire sont limitées par le manque de données probantes de grande qualité. Les études observationnelles et les rapports de cas ne fournissent pas de données probantes à l'encontre de la poursuite de la buprénorphine dans la période périopératoire, en particulier quand la dose journalière par voie sublinguale est < 16 mg. Chez les patients présentant un risque significatif de rechute, comme ceux ayant des antécédents récents de TUO, l'arrêt de la buprénorphine devrait être solidement justifié avec le soutien des préférences des patients et des équipes chirurgicales. Les futures études nécessitent une normalisation du rapport des doses médianes, des détails sur les voies d'administration, de la posologie et de sa modification et des taux de rechute, en incluant aussi, chaque fois que possible, les taux de morbidité et mortalité à long terme.

Managing opioid use disorder in primary care: PEER simplified guideline.

OBJECTIVE: To use the best available evidence and principles of shared, informed decision making to develop a clinical practice guideline for a simplified approach to managing opioid use disorder (OUD) in primary care. METHODS: Eleven health care and allied health professionals representing various practice settings, professions, and locations created a list of key questions relevant to the management of OUD in primary care. These questions related to the treatment setting, diagnosis, treatment, and management of comorbidities in OUD. The questions were researched by a team with expertise in evidence evaluation using a series of systematic reviews of randomized controlled trials. The Guideline Committee used the systematic reviews to create recommendations. RECOMMENDATIONS: Recommendations outline the role of primary care in treating patients with OUD, as well as pharmacologic and psychotherapy treatments and various prescribing practices (eg, urine drug testing and contracts). Specific recommendations could not be made for management of comorbidities in patients with OUD owing to limited evidence. CONCLUSION: The recommendations will help simplify the complex management of patients with OUD in primary care. They will aid clinicians and patients in making informed decisions regarding their care.

Endocarditis in the setting of IDU: multidisciplinary management.

PURPOSE OF REVIEW: The purpose of this article is to provide a brief overview of the medical and surgical management of infective endocarditis secondary to IDU, with a focus on the underlying substance use disorder. RECENT FINDINGS: Patients with infective endocarditis secondary to IDU are often young with unique comorbidities including mental illness, chronic hepatitis C, HIV infection, which are often compounded by limited social and familial supports. The focus of management has been treatment of endocarditis using IV antibiotics alongside surgery. Surgical outcomes compare favorably with those of infective endocarditis in the general population but long-term outcomes of IDUs are significantly worse. This is primarily due to the high rate of recidivism of drug use and the risk of prosthetic valve infective endocarditis. Contemporary management of addiction utilizes an integrative approach, combining both pharmacologic and nonpharmacologic strategies while remaining patient-centered. Given the complexity of care required, we advocate for a multidisciplinary team-based approach including psychiatry, infectious disease, cardiology, cardiac surgery and social services. SUMMARY: Infective endocarditis secondary to IDU remains a medical and surgical challenge with dismal outcomes. Here we offer practical suggestions on the multidisciplinary management of this challenging and high-risk patient cohort.

Prise en charge du trouble de consommation d'opioïdes en première ligne: Lignes directrices simplifiées de PEER.

OBJECTIF: Utiliser les meilleures données probantes et les meilleurs principes de prise de décision partagée et éclairée à notre disposition pour élaborer des lignes directrices de pratique clinique visant une approche simplifiée de prise en charge du trouble de consommation d'opioïdes (TCO) en première ligne. MÉTHODES: Onze professionnels de la santé et professionnels paramédicaux représentant divers milieux de pratique, professions et lieux ont créé une liste de questions pertinentes à la prise en charge du TCO en première ligne. Ces questions étaient liées au contexte thérapeutique, au diagnostic, au traitement et à la prise en charge des comorbidités dans le TCO. Les questions ont été étudiées par une équipe expérimentée dans l'évaluation des données probantes à l'aide d'une série de revues systématiques d'études randomisées et contrôlées. Les recommandations émises par le comité des lignes directrices reposent sur les revues systématiques. RECOMMANDATIONS: Les recommandations font ressortir le rôle des soins primaires dans le traitement des patients aux prises avec un TCO, de même que les traitements pharmacologiques et psychothérapies et les diverses pratiques de prescription (p. ex. test urinaire de dépistage de drogues et contrats). Aucune recommandation précise n'a pu être faite sur la prise en charge des comorbidités chez les patients aux prises avec un TCO, en raison des données probantes limitées. CONCLUSION: Les recommandations contribueront à simplifier la prise en charge des cas complexes de TCO en première ligne. Elles aideront tant les cliniciens que les patients à prendre des décisions éclairées au sujet de leurs soins.

Approach and Management of Alcohol Withdrawal Syndrome in Operative Head and Neck Cancer Patients.

Postoperative head and neck cancer patients are at increased risk for alcohol withdrawal syndrome. Literature has shown that in this patient population, alcohol withdrawal is associated with an increase in postoperative medical and surgical complications, length of hospitalization, and hospital-related costs. Harm reduction and addiction medicine philosophies can reduce morbidity and mortality, but have not been fully validated in perioperative surgical management for head and neck cancer. This commentary synthesizes key principles of addiction medicine and current strategies that Otolaryngology-Head and Neck Surgery surgeons can consider in their perioperative assessment and management of alcohol withdrawal syndrome in their patients.

Use of Injectable Opioid Agonist Therapy in a In-Patient Setting for a Pregnant Patient With Opioid Use Disorder: A Case Report.

BACKGROUND: In the era of highly potent illicit opioids, such as fentanyl and carfentanil, injectable opioid agonist treatment (iOAT) is an effective treatment for those with severe and treatment-refractory opioid use disorder. Untreated opioid use disorder in pregnancy can lead to maternal and neonatal morbidity and mortality. There are currently limited reports on the use of iOAT in pregnant women. The in-patient setting may provide an opportunity to pregnant women for stabilization with iOAT where first line therapies have been ineffective. CASE SUMMARY: We report a case of a pregnant individual who engaged in daily intravenous fentanyl who was admitted to the hospital at 29 weeks gestation for stabilization with iOAT, methadone, and slow-release oral morphine. Before admission, she endured 6 opioid overdoses in her pregnancy and continued to use illicit intravenous opioids in the community despite high dose methadone combined with slow-release oral morphine. Her withdrawal symptoms and cravings were ameliorated with hydromorphone 90 mg IM/IV BID, methadone 135 mg daily, and morphine sulfate sustained release 600 mg daily. With this regimen, she was able to reduce her intravenous fentanyl use to a single episode during her hospitalization. She completed her pregnancy in hospital, delivering a full-term live infant after receiving comprehensive prenatal care. DISCUSSION: This case report highlights iOAT as an option during pregnancy and describes the in-patient setting as appropriate to retain high-risk patients in care. This approach may benefit those who are refractory to standard opioid agonist treatment, the numbers of whom may be rising as tolerance to the illicit supply increases.

Infective Endocarditis Secondary to Injection Drug Use: A Survey of Canadian Cardiac Surgeons.

BACKGROUND: Injection drug use-associated infective endocarditis (IDU-IE) is a growing epidemic. The objective of this survey was to identify the beliefs and practice patterns of Canadian cardiac surgeons regarding surgical management of IDU-IE. METHODS: A 30-question survey was developed by a working group and distributed to all practicing adult cardiac surgeons in Canada. Data were analyzed using descriptive statistics. RESULTS: Of 146 surgeons, 94 completed the survey (64%). Half of surgeons (49%) would be less likely to operate on patients with IE if associated with IDU. In the case of prosthetic valve IE owing to continued IDU, 36% were willing to reoperate once and 14% were willing to reoperate twice or more. Most surgeons required commitments from patients before surgery (73%), and most referred patients to addiction services (81%). Some surgeons would offer a Ross procedure (10%) or homograft (8%) for aortic valve IE, and 47% would consider temporary mechanical circulatory support. Whereas only 17% of surgeons worked at an institution with an endocarditis team, 71% agreed that there was a need for one at each institution. Most surgeons supported the development of IDU-IE-specific guidelines (80%). CONCLUSIONS: Practice patterns and surgical management of IDU-IE vary considerably across Canada. Areas of clinical unmet needs include the development of a formal addiction services referral protocol for patients, the development of an interdisciplinary endocarditis team, as well as the creation of IDU-IE clinical practice guidelines.

Perioperative Pain and Addiction Interdisciplinary Network (PAIN): protocol of a practice advisory for the perioperative management of buprenorphine using a modified Delphi process.

INTRODUCTION: The ongoing opioid epidemic has necessitated increasing prescriptions of buprenorphine, which is an evidence-based treatment for opioid use disorder, and also shown to reduce harms associated with unsafe opioid administration. A systematic review of perioperative management strategies for patients taking buprenorphine concluded that there was little guidance for managing buprenorphine perioperatively. The aim of this project is to develop consensus guidelines on the optimal perioperative management strategies for this group of patients. In this paper, we present the design for a modified Delphi technique that will be used to gain consensus among patients and multidisciplinary experts in addiction, pain, community and perioperative medicine. METHODS AND ANALYSIS: A national panel of experts identified by perioperative, pain and/or addiction systematic review authorship established an international profile in perioperative, pain and/or addiction research, community clinical excellence and by peer referral. A steering group will develop the first round with a list of indications to be rated by the panel of national experts, patients and allied healthcare professionals. In round 1, the expert panel will rate the appropriateness of each individual item and provide additional suggestions for revisions, additions or deletions. The definition of consensus will be set a priori. Consensus will be gauged for both appropriateness and inappropriateness of treatment strategies. Where an agreement is not reached and items are suggested for addition/deletion/modification, round 2 will take place over teleconference in order to obtain consensus. ETHICS AND DISSEMINATION: Institutional research ethics board provided a waiver for this modified Delphi protocol. We plan on developing a national guideline for the management of patients taking buprenorphine in the perioperative period that will be generalisable across three sets of preoperative diagnoses including opioid use disorder and/or co-occurring pain disorders. The findings will be published in peer-reviewed publications and conference presentations.

Characterization of lymphoproliferative lesions of the conjunctiva: immunohistochemical and molecular genetic studies.

BACKGROUND: Conjunctival lymphoproliferative lesions have not been selected for independent analysis with newer immunohistochemical and molecular genetic techniques to highlight their unique profile. METHODS: Retrospective case series examined biopsies from 16 consecutive patients with conjunctival lymphoproliferative lesions. The histopathologic, immunohistochemical, and molecular genetic features were characterized, as well as the frequency of tumour type, prognostic implications, clinical features, and treatments offered. RESULTS: The diagnosis was lymphoma in 12 cases, atypical lymphoid hyperplasia (ALH) in 1 case, and reactive lymphoid hyperplasia (RLH) in 3 cases. The primary lymphomas consisted of 4 mucosa-associated lymphoid tissue lymphomas (MALTL), 1 follicular lymphoma (FL), 2 diffuse large B-cell lymphomas (DLBCLs), 1 lymphoplasmacytic lymphoma, and 1 T-cell lymphoma. Primary lymphomas were treated with radiation (n = 7), surgery (n = 1), and topical chemotherapy (n = 1). Complete remission was achieved in 8 of 9 primary lymphomas. Two cases of recurrence to the other conjunctiva were treated with radiation and both remained disease free. Secondary lymphomas included 2 DLBCL and 1 MALTL. Complete remission was seen in 2 patients after radiation plus chemotherapy, while the patient treated with chemotherapy alone was lost to follow-up. The 1 case of ALH presented bilaterally and achieved complete remission after topical chemotherapy treatments. The 3 RLH cases were surgically managed and 2 of the 3 recurred and were subsequently excised. Eleven lymphomas were of B-cell lineage by immunophenotyping. Molecular genetic studies of immunoglobulin heavy chain (IgH) gene rearrangement by polymerase chain reaction (PCR) showed clonal bands in 6 of 12 lymphomas, 1 of 3 RLH (polyclonal by immunophenotyping) and 1 ALH. BCL2-IgH [t(14;18)] rearrangement was seen in 8 of 12 cases (1 FL, 3 DLBCLs, 4 MALTLs) by real-time quantitative PCR. INTERPRETATION: Conjunctival lymphomas are predominantly B-cell type with a high prevalence of MALTL. An unexpected finding was the BCL2-IgH rearrangement seen in 4 of 5 MALTL cases in our series. The significance of this remains unclear.

MPTP induces intranuclear rodlet formation in midbrain dopaminergic neurons.

Neuronal intranuclear rodlets (INRs; rodlets of Roncoroni) have been known to neuroanatomists since the turn of the century. However, the functional and/or pathological significance of these structures has remained enigmatic. We recently demonstrated that these structures are immunoreactive for class III beta tubulin and for glucocorticoid receptor. Moreover, they are markedly reduced in the temporal cortex of patients with Alzheimer's disease relative to age-matched controls and those with dementia with Lewy bodies, thereby implicating these structures in neurodegenerative disease pathogenesis. The present report represents an experimental pilot study to investigate the possible involvement of INRs in Parkinson's disease (PD). Specifically, we demonstrate significantly increased INRs in dopaminergic neurons in the substantia nigra pars compacta and ventral tegmental area in mice treated with the selective catecholaminergic neurotoxin MPTP, relative to saline-treated controls. We have hypothesized that INRs represent an intranuclear sequestrum of monomeric beta-tubulin and that their alteration in neurodegeneration may reflect disrupted or abnormal microtubule dynamics. We propose that the increased formation of INRs is related to the demonstrated ability of MPTP to cause microtubule disruption. Because tubulin has also been implicated in the pathogenesis of human PD, it is possible that the results of this study will have important implications for this most common neurodegenerative movement disorder.

Lymphoproliferative lesions of the lacrimal gland: clinicopathological, immunohistochemical and molecular genetic analysis.

BACKGROUND: Lacrimal gland lymphoproliferative disorders are usually classified as orbital adnexal tumours. Because the lacrimal gland is the only orbital structure with native lymphocytes, we examined cases with primary involvement of the gland. METHODS: The 14 cases were selected from a review of all cases in the surgical pathology files of the Ottawa Hospital between 1992 and 2003. The lesions were categorized according to the latest World Health Organization classification of tumours of lymphoid tissues. We conducted a clinical, histopathological, immunohistochemical, immunophenotypic and molecular genetic analysis of the cases. RESULTS: The 8 female and 6 male patients, aged 20 to 88 (mean 60) years, were followed for an average of 4 years (range 11 months to 13 years). All presented with supratemporal orbital swelling. The 5 primary lymphomas, of mucosa-associated lymphoid tissue (MALT), were confined to the lacrimal gland (stage IE); 1 tumour transformed to diffuse large B-cell lymphoma, necessitating chemotherapy, and the other 4 were treated with radiation. One of the 5 patients had previously had Sjögren's syndrome. The 6 secondary lymphomas (4 follicular) presented either concurrently with systemic lymphoma or up to 12 years afterwards and were treated in a variety of ways; all the patients had an orbital relapse. At the last follow-up assessment, 6 of the patients with lymphoma had no evidence of disease, 3 were alive with disease, 2 had died (1 of lymphoma, the other with no evidence of disease), and the status of 1 patient was not known. Of the 3 patients with reactive proliferations, 2 had reactive lymphoid hyperplasia (associated with Sjögren's syndrome in 1), and 1 had Rosai-Dorfman disease. All 9 lymphomas that underwent molecular genetic analysis were of B-cell lineage, and 8 had a monoclonal rearrangement in the immunoglobulin heavy-chain gene (IgH); the 9th lymphoma showed an oligoclonal rearrangement. One lymphoma showed the t(14;18) translocation, typical of follicular lymphoma; no lymphoma showed the t(11;18) translocation, commonly found in MALT lymphoma (but only 2 cases were studied). Molecular genetic analysis was performed in 2 of the cases of reactive lymphoid hyperplasia: monoclonal IgH rearrangement was detected in 1 case (the patient with Sjögren's syndrome), oligoclonal rearrangement in the other. INTERPRETATION: Lacrimal gland lymphomas are B-cell tumours that develop in older adults. Primary tumours, a hIgH proportion of which have MALT characteristics, have a favourable prognosis. Molecular genetic studies may be useful when morphologic and immunophenotypic studies give equivocal results.

Regulation of axotomy-induced dopaminergic neuron death and c-Jun phosphorylation by targeted inhibition of cdc42 or mixed lineage kinase.

Mechanical transection of the nigrostriatal dopamine pathway at the medial forebrain bundle (MFB) results in the delayed degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). We have previously demonstrated that c-Jun activation is an obligate component of neuronal death in this model. Here we identified the small GTPase, cdc42, and mixed lineage kinases (MLKs) as upstream factors regulating neuronal loss and activation of c-Jun following MFB axotomy. Adenovirus-mediated expression of a dominant-negative form of cdc42 in nigral neurons blocked MFB axotomy-induced activation (phosphorylation) of MAP kinase kinase 4 (MKK4) and c-Jun, resulting in attenuation of SNpc neuronal death. Pharmacological inhibition of MLKs, MKK4-activating kinases, significantly reduced the phosphorylation of c-Jun and abrogated dopaminergic neuronal degeneration following MFB axotomy. Taken together, these findings suggest that death of nigral dopaminergic neurons following axotomy can be attenuated by targeting cell signaling events upstream of c-Jun N-terminal mitogen-activated protein kinase/c-Jun.