Opioids and obstructive sleep apnea.

Opioids are widely prescribed for pain management, and it is estimated that 40% of adults in the United States use prescription opioids every year. Opioid misuse leads to high mortality, with respiratory depression as the main cause of death. Animal and human studies indicate that opioid use may lead to sleep-disordered breathing. Opioids affect control of breathing and impair upper airway function, causing central apneas, upper airway obstruction, and hypoxemia during sleep. The presence of obstructive sleep apnea (OSA) increases the risk of opioid-induced respiratory depression. However, even if the relationship between opioids and central sleep apnea is firmly established, the question of whether opioids can aggravate OSA remains unanswered. While several reports have shown a high prevalence of OSA and nocturnal hypoxemia in patients receiving a high dose of opioids, other studies did not find a correlation between opioid use and obstructive events. These differences can be attributed to considerable interindividual variability, divergent effects of opioids on different phenotypic traits of OSA, and wide-ranging methodology. This review will discuss mechanistic insights into the effects of opioids on the upper airway and hypoglossal motor activity and the association of opioid use and obstructive sleep apnea. CITATION: Freire C, Sennes LU, Polotsky VY. Opioids and obstructive sleep apnea. J Clin Sleep Med. 2022;18(2):647-652.

Designer Receptors Exclusively Activated by Designer Drugs Approach to Treatment of Sleep-disordered Breathing.

Rationale: Obstructive sleep apnea is recurrent upper airway obstruction caused by a loss of upper airway muscle tone during sleep. The main goal of our study was to determine if designer receptors exclusively activated by designer drugs (DREADD) could be used to activate the genioglossus muscle as a potential novel treatment strategy for sleep apnea. We have previously shown that the prototypical DREADD ligand clozapine-N-oxide increased pharyngeal diameter in mice expressing DREADD in the hypoglossal nucleus. However, the need for direct brainstem viral injections and clozapine-N-oxide toxicity diminished translational potential of this approach, and breathing during sleep was not examined.Objectives: Here, we took advantage of our model of sleep-disordered breathing in diet-induced obese mice, retrograde properties of the adeno-associated virus serotype 9 (AAV9) viral vector, and the novel DREADD ligand J60.Methods: We administered AAV9-hSyn-hM3(Gq)-mCherry or control AAV9 into the genioglossus muscle of diet-induced obese mice and examined the effect of J60 on genioglossus activity, pharyngeal patency, and breathing during sleep.Measurements and Main Results: Compared with control, J60 increased genioglossus tonic activity by greater than sixfold and tongue uptake of 2-deoxy-2-[18F]fluoro-d-glucose by 1.5-fold. J60 increased pharyngeal patency and relieved upper airway obstruction during non-REM sleep.Conclusions: We conclude that following intralingual administration of AAV9-DREADD, J60 can activate the genioglossus muscle and improve pharyngeal patency and breathing during sleep.

Intranasal Leptin Prevents Opioid-induced Sleep-disordered Breathing in Obese Mice.

Respiratory depression is the main cause of morbidity and mortality associated with opioids. Obesity increases opioid-related mortality, which is mostly related to comorbid obstructive sleep apnea. Naloxone, a µ-opioid receptor blocker, is an effective antidote, but it reverses analgesia. Like humans with obesity, mice with diet-induced obesity hypoventilate during sleep and develop obstructive sleep apnea, which can be treated with intranasal leptin. We hypothesized that intranasal leptin reverses opioid-induced sleep-disordered breathing in obese mice without decreasing analgesia. To test this hypothesis, mice with diet-induced obesity were treated with morphine at 10 mg/kg subcutaneously and with leptin or placebo intranasally. Sleep and breathing were recorded by barometric plethysmography, and pain sensitivity was measured by the tail-flick test. Excitatory postsynaptic currents were recorded in vitro from hypoglossal motor neurons after the application of the µ-opioid receptor agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin and leptin. Morphine dramatically increased the frequency of apneas and greatly increased the severity of hypoventilation and obstructive sleep apnea. Leptin decreased the frequency of apneas, improved obstructive sleep apnea, and completely reversed hypoventilation, whereas morphine analgesia was enhanced. Our in vitro studies demonstrated that [D-Ala2, N-MePhe4, Gly-ol]-enkephalin reduced the frequency of excitatory postsynaptic currents in hypoglossal motoneurons and that application of leptin restored excitatory synaptic neurotransmission. Our findings suggest that intranasal leptin may prevent opioid respiratory depression during sleep in patients with obesity receiving opioids without reducing analgesia.

Neurostimulation Treatment of OSA.

Over the past 30 years, hypoglossal nerve stimulation has moved through a development pathway to become a viable treatment modality for patients with OSA. Initial pilot studies in animals and humans laid the conceptual foundation for this approach, leading to the development of fully implantable stimulating systems for therapeutic purposes. These devices were then shown to be both safe and efficacious in feasibility studies. One such closed-loop stimulating device was found to be effective in treating a limited spectrum of apneic patients and is currently approved by the US Food and Drug Administration for this purpose. Another open-loop stimulating system is currently being rigorously tested in a pivotal trial. Collectively, clinical trials of hypoglossal nerve stimulating systems have yielded important insights that can help optimize therapeutic responses to hypoglossal nerve stimulation. These insights include specific patient selection criteria and methods for delivering stimulation to specific portions of the hypoglossal nerve and/or genioglossus muscle. New approaches for activating efferent and afferent motor pathways are currently in early-stage laboratory development and hold some long-term promise as a novel therapy.

Chemogenetic stimulation of the hypoglossal neurons improves upper airway patency.

Obstructive sleep apnea (OSA) is characterized by recurrent upper airway obstruction during sleep. OSA leads to high cardiovascular morbidity and mortality. The pathogenesis of OSA has been linked to a defect in neuromuscular control of the pharynx. There is no effective pharmacotherapy for OSA. The objective of this study was to determine whether upper airway patency can be improved using chemogenetic approach by deploying designer receptors exclusively activated by designer drug (DREADD) in the hypoglossal motorneurons. DREADD (rAAV5-hSyn-hM3(Gq)-mCherry) and control virus (rAAV5-hSyn-EGFP) were stereotactically administered to the hypoglossal nucleus of C57BL/6J mice. In 6-8 weeks genioglossus EMG and dynamic MRI of the upper airway were performed before and after administration of the DREADD ligand clozapine-N-oxide (CNO) or vehicle (saline). In DREADD-treated mice, CNO activated the genioglossus muscle and markedly dilated the pharynx, whereas saline had no effect. Control virus treated mice showed no effect of CNO. Our results suggest that chemogenetic approach can be considered as a treatment option for OSA and other motorneuron disorders.

Study of the association between human leukocyte antigens (HLA) and pemphigus vulgaris in Brazilian patients.

BACKGROUND: Pemphigus vulgaris is a mucocutaneous blistering autoimmune disease that manifests as painful blisters or erosions on the skin and/or mucosal surfaces. IgG autoantibodies target desmoglein, playing a major role in disease pathogenesis. Genetic predisposal to pemphigus vulgaris, especially the HLA DR and DQ alleles, has been known since the 1980s. The unique constitution of the Brazilian population favors exploratory genetic studies. METHODS: The study group included 51 patients with a confirmed diagnosis of pemphigus vulgaris from a tertiary hospital in Sao Paulo city, Sao Paulo, southeast Brazil. DNA was extracted from peripheral blood, and HLA A, B, C, DR, and DQ typing was performed. The control group was composed of a database of 297 deceased donors from the city of São Paulo typed with the same method. The statistical significance level was adjusted using the Bonferroni correction depending on the phenotypic frequencies evaluated for HLA A, HLA B, HLA C, HLA DRB1, DQA1, and HLA DQB1. RESULTS: The alleles HLA-B*57, HLA-C*15, HLA-DRB1*04:02, HLA-DRB1*08:04, HLA-DRB1*14:01, DQA1*03:01, DQB1*03:02, and DQB1*05:03 were associated with susceptibility. Alleles HLA DRB1*04:02 and HLA-DRB1*14:01 and their respective haplotypes DRB1*04-DQA1*03:01-DQB1*03:02, and DRB1*14-DQA1*01:01-DQB1*05:03 conferred a risk of the disease. CONCLUSIONS: The DRB1*04:02 and DQB1*05:03 alleles are associated with pemphigus vulgaris in our study as well as in various populations. The association with HLA-DRB1*08:04 in our study was confirmed to be specific to this allele and not to linkage disequilibrium to any adjacent gene. The association between HLA-B*57 and pemphigus vulgaris is reported for the first time in the present study.

Mandibular reconstruction with a fibular osteocutaneous free flap in an 8-month-old girl with a 12-year follow-up.

The purpose of this article is to describe a case of an 8-month-old girl who was diagnosed with a melanotic neuroectodermal tumor and was submitted to a right hemimandibulectomy and immediate reconstruction with a fibular osteocutaneous free flap. At 12-year follow-up, the longest reported in a patient this young, the transferred bone had grown much like the native mandible, and the patient had adequate mandibular contour and function. No revisions were needed, although orthopedic surgery was performed to correct an ankle valgus deviation on the donor leg. It is the opinion of the authors that microsurgical mandible reconstruction in very young patients is efficient and that the surrounding structures contribute to the remodeling of the bone segment to achieve characteristics similar to those of the native mandible.

Individually customized implants for laryngoplasty--are they possible?

OBJECTIVE: To standardize the design of individually fitted implants based on computed tomographic (CT) images for use in medialization laryngoplasty without intraoperative voice monitoring. STUDY DESIGN: Prospective tomographic and anatomical experimental study of 10 human cadaveric larynges. METHODS: CT scans of 10 excised human larynges were analyzed to define the shape and size of ideal implants for medialization laryngoplasty. Silicone implants were designed according to CT parameters and used in simulated laryngoplasties in the laryngeal specimens. The efficacy of each implant in providing adequate medialization of the vocal fold was evaluated. RESULTS: Diverse shapes and sizes of implants were obtained, reflecting variations in laryngeal anatomy. The implants enabled regular medialization of the entire extent of the free border of the vocal fold, including its posterior aspect. Medialization was considered adequate in all cases. CONCLUSIONS: This method proved to be a simple and efficient way to design individualized implants for medialization laryngoplasty, regardless of the size and shape of the larynx. LEVEL OF EVIDENCE: Not available.

Endonasal endoscopic exposure of the internal carotid artery: an anatomical study.

OBJECTIVES/HYPOTHESIS: The aim of this work was to define the anatomical landmarks, limitations, and difficulties of obtaining internal carotid artery (ICA) exposure via endonasal endoscopic approaches (EEA). STUDY DESIGN: Cadaveric descriptive study. METHODS: The ICA was dissected via EEA in 10 cadaveric specimens (20 sides) prepared with intravascular injections of colored silicone. We carried the ICA dissection from the cavernous to the distal parapharyngeal segments through a transpterygoid corridor. RESULTS: The transpterygoid approach provided adequate exposure of the lacerum and horizontal petrous ICA. Additional exposure of the ICA and the infrapetrous area required resection of the eustachian tube (ET) and the fibrocartilaginous tissue of the foramen lacerum after a medial maxillectomy and resection of the pterygoid plates. The main anatomical landmarks to the corresponding ICA segment include: the vidian nerve that points to the lacerum and horizontal segments, the mandibular nerve (V3) that heralds the petrous segment, the foramen ovale and the ET that signal toward the carotid canal, and the posterior trunk of the mandibular nerve (V3) and the ET that mark the parapharyngeal segment. CONCLUSIONS: EEAs provide access to the ICA from its cavernous to the distal parapharyngeal segments. A stepwise approach is critical to its exposure and control. Surgeons must be aware of its frequently tortuous three-dimensional course and the intimate relation of the vessel to the carotid canal and the cartilage of the foramen lacerum.

Endoscopic anatomy of the palatovaginal canal (palatosphenoidal canal): a landmark for dissection of the vidian nerve during endonasal transpterygoid approaches.

OBJECTIVES/HYPOTHESIS: Demonstrate the endoscopic anatomy of the palatovaginal (PV) canal and artery for identification and dissection of the vidian nerve during endoscopic transpterygoid approaches. Evaluate the length of the PV canal and its relation with the vidian nerve. Show that the traditionally known PV canal is a misnomer and should be renamed. STUDY DESIGN: Experimental study: anatomical and radiological. METHODS: Dissection of eight cadaveric heads was performed to demonstrate the endoscopic anatomy of the PV canal. Computed tomography scan analysis of 20 patients was used to evaluate the length of the PV canal, the angle formed between this canal and the vidian nerve, and the distance between the vidian canal and the PV canal. Study of 10 dry skull bases was performed to verify the structures involved in the formation of the PV canal. RESULTS: Anatomic steps and foundations for dissection of the vidian nerve using the PV canal as a landmark were described. The mean length of the PV canal was 7.15 mm. The mean proximal distance between the vidian and the PV canal was 1.95 mm, and the mean distal distance was 4.14 mm. The mean angle between those canals was 48 degrees. The osteology study showed the vaginal process of the sphenoid bone did not contribute to the formation of the PV canal. CONCLUSIONS: Our anatomic investigations, radiologic studies, and surgical experience demonstrate the important anatomic relationship of the PV canal with the vidian canal and the relevance of the PV canal as a surgical landmark in endoscopic endonasal transpterygoid approaches. Anatomically, PV canal is a misnomer and should be replaced with palatosphenoidal canal.

Study of the nasoseptal flap for endoscopic anterior cranial base reconstruction.

OBJECTIVES/HYPOTHESIS: Measure the dimensions of the nasoseptal (NS) flap and the anterior skull base (ASB) defect. Verify whether the flap is sufficient to cover the defect. Study the anatomy of the septal artery (SA). STUDY DESIGN: Anatomical and radiological study. METHODS: After endoscopic craniofacial resection, sufficiency of the flap to cover the ASB defect was assessed. The SA was dissected. The number of branches in the pedicle and the distance between the artery and the sphenoid ostium were noted. Radiologic study analyzing CT scans of 30 patients for comparison among measurements of the NS flap and the ASB defect was performed. RESULTS: In all cases the flap was sufficient to cover the ASB. Two branches of the SA were found in the pedicle in 71.4%. The distance between the SA and the sphenoid ostium was 9.3 mm. The reconstruction area of the flap (17.12 cm(2) ) was larger than the defect area (8.64 cm(2) ) (P < .001). The difference between the superior length of the flap and the anterior-posterior distance of the defect was ≤ 5 mm in 26.7%. Comparison between the anterior flap width and the anterior defect width revealed that in 33% the difference was ≤ 5 mm. CONCLUSIONS: The dimensions of NS flap are sufficient to cover completely the ASB defect. The anterior edge of the defect presents increased risk for failure in coverage. Additional width adding the nasal floor mucosa to the flap is important to decrease the risk of gap in the anterior orbit-orbit defect. It is more common to find two branches of the SA in the pedicle.

Collagen type I, collagen type III, and versican in vocal fold lamina propria.

OBJECTIVE: To analyze the distributions of collagen type I, collagen type III, and versican in the lamina propria of the human vocal fold. DESIGN: Cross-sectional analysis of cadaveric vocal folds of adult human larynges. SETTING: Academic tertiary referral center. SUBJECTS: Larynges harvested at autopsy from 10 adult men and 10 adult women. MAIN OUTCOME MEASURES: Immunohistochemical reactions were performed using antihuman monoclonal antibodies to analyze the expression of collagen type I, collagen type III, and versican. RESULTS: Collagen type I density was lower in the intermediate layer compared with the superficial and deep layers of vocal folds. Collagen type III density was lower in the intermediate layer compared with the deep layer. Versican density was lower in the superficial layer compared with the intermediate and deep layers. Versican density was lower in the lamina propria of women compared with men; this difference was noted in the superficial layer only. There was a positive correlation between collagen type III and versican densities within the lamina propria. CONCLUSION: Collagen type I, collagen type III, and versican are distributed differently within the lamina propria layers of the adult vocal folds.

The presence of a vocal ligament in fetuses: a histochemical and ultrastructural study.

Although it is currently believed that the vocal ligament of humans undergoes considerable development postnatally, there is no consensus as to the age at which it first emerges. In the newborn infant, the lamina propria has been described as containing a sparse collection of relatively unorganized fibres. In this study we obtained larynges from autopsy of human fetuses aged 7-9 months and used light and electron microscopy to study the collagenous and elastic system fibres in the lamina propria of the vocal fold. Collagen fibres were viewed using the Picrosirius polarization method and elastic system fibres were stained using Weigert's resorcin-fuchsin after oxidation with oxone. The histochemical and electron microscopic observations were consistent, showing collagen populations with an asymmetric distribution across different compartments of the lamina propria. In the central region, the collagen appeared as thin, weakly birefringent, greenish fibres when viewed using the Picrosirius polarization method, whereas the superficial and deep regions contained thick collagen fibres that displayed a strong red or yellow birefringence. These findings suggest that the thin fibres in the central region consist mainly of type III collagen, whereas type I collagen predominates in the superficial and deep regions, as has been reported in studies of adult vocal folds. Similarly, elastic system fibres showed a differential distribution throughout the lamina propria. Their distribution pattern was complementary to that of collagen fibres, with a much greater density of elastic fibres apparent in the central region than in the superficial and deep regions. This distribution of collagen and elastic fibres in the fetal vocal fold mirrors that classically described for the adult vocal ligament, suggesting that a vocal ligament has already begun to develop by the time of birth. The apparently high level of organization of connective tissue components in the newborn is in contrast to current hypotheses that argue that the mechanical stimuli of phonation are essential to the determination of the layered structure of the lamina propria and suggests that genetic factors may play a more significant role in the development of the vocal ligament than previously believed.

T-shaped microsuture: a new suture technique for laryngeal microsurgery.

UNLABELLED: To describe a new suture technique for laryngeal microsurgery and to test its applicability in human cadaver larynges. The new technique was experimentally tested in freshly excised human larynges fixed to a larynx holder appropriate for the simulation of laryngeal microsurgery. A mucosal flap was created in the vocal fold for the fabrication of a pocket for subepithelial fat implantation, and the wound edges were then brought together and sutured using the proposed technique. The time necessary for suture was measured with a stopwatch for five successive sutures performed by one of the surgeons. The presence or absence of mucosal rupture was determined for five sutures performed by two surgeons, for a total of 10 sutures. The sutures were performed without the help of an assistant, with no laceration of the mucosa being observed in any of the attempts, and within a relatively short period of time even without previous training. The sutures performed permitted the implanted fat to remain stable under the mucosal flap. CONCLUSIONS: the new suture technique is an easy procedure, which can be performed by a single surgeon under microscopic vision, with a low risk of tissue rupture. The technique does not markedly prolong the duration of surgery and a single suture thread can be used for the fabrication of more than one stitch.

Disarrangement of collagen fibers in Reinke's edema.

OBJECTIVE/HYPOTHESIS: To describe the arrangement of collagen fibers in the superficial layer of the lamina propria of the vocal folds with Reinke' edema. STUDY DESIGN: Cross sectional analysis of the lamina propria of the vocal folds with Reinke's edema (RE). METHOD: The picrosirius polarization method was used to study the arrangement of collagen fiber. Findings of collagen disarrangement were categorized semiquantitatively and correlated with RE severity, age, cigarette smoking and duration of dysphonia. RESULTS: Analysis of 20 specimens of vocal folds with RE showed that the intertwined network of collagen fibers resembling a wicker-basket normally observed in vocal folds was disarranged in RE. The collagen fibers were loosely arranged, fragmented and intermixed with varying amounts of myxoid stroma. Moderate and large areas of disarrangement (90% of cases) predominated. Collagen fiber arrangement in the region underneath the epithelium was better preserved when compared with fibers in the deeper region of the superficial layer of the lamina propria. There was a statistical difference in collagen disarrangement between grade II and grade III severity (P = .007) that appeared to be due to the large areas of disarrangement observed in 73% of patients with grade III severity and in 44% of grade II severity. Age was the only variable correlated with collagen fiber disarrangement (r = 0.47, P = .037). CONCLUSION: Our findings suggest that the flexible framework which maintains the uniformity of the lamina propria was lost in RE caused by the disarrangement of the collagen fibers.

Collagen fiber and versican distribution within the lamina propria of fetal vocal folds.

OBJECTIVES: To analyze the presence and distribution of collagen fibers and versican in human vocal fold lamina propria of fetal larynges. STUDY DESIGN: Cross sectional analysis of cadaveric vocal folds of human fetuses. METHODS: Seven fetal larynges obtained from 28- to 36-week-old fetuses were analyzed with the Picrosirius-polarization method, immunohistochemistry, and image analysis. RESULTS: Collagen fibers within the lamina propria exhibited a monolaminar distribution pattern and spatial arrangement in "wicker basket." Versican distribution was larger in the superficial and intermediate layers when compared to the deep layer. CONCLUSION: Our findings suggest that collagen and versican distribution and arrangement within the lamina propria in the developing fetus are important for vocalization at birth.

Tissue maturation correlating to clinical manifestations in juvenile angiofibroma.

OBJECTIVES: Juvenile nasopharyngeal angiofibroma is a rare benign tumor that affects young male patients and shows a characteristic development from its origin. It is not a true neoplasm, but shows features of vascular processes, developing into a more fibrous condition. The aim of this study was to correlate the clinical manifestations and the histologic findings of the tumor. METHODS: Thirty-six patients without previous treatment were studied. We correlated the incidence and duration of the clinical manifestations (nasal obstruction, epistaxis, nasal and/or pharyngeal tumor, and facial deformity) and morphometric histologic analyses of the central region of the tumor (number, caliber, and presence of muscle cells in the vessel wall, and tissue maturity and cellularity). RESULTS: The duration of nasal obstruction, the presence of nasal and/or pharyngeal tumor, and facial deformity were significantly correlated with the number of vessels, the tissue maturation, and the cellularity of the tumor. Epistaxis showed a strong correlation with the presence of muscle fibers in the vessels. CONCLUSIONS: There are correlations between the duration of the clinical manifestations and histologic maturation in the central portion of the tumor.

Glioma nasal: relato de três casos e revisão de literatura / Nasal glioma: report of 3 cases and literature review

Glioma Nasal é uma malformação congênita rara, benigna e diagnosticada habitualmente logo após o nascimento, que requer tratamento precoce para evitar deformidades faciais. Säo relatados três casos de pacientes com diagnóstico de Glioma Nasal em acompanhamento no Departamento de Otorrinolaringologia do Hospital das Clínicas da Faculdade de Medicina da USP, com descriçäo, para cada caso, dos exames subsidiários, do tratamento empregado e de sua evoluçäo. O primeiro caso é do sexo feminino, que apresentava uma massa sólida que se exteriorizava pela fossa nasal esquerda. O segundo paciente era do sexo masculino e apresentava uma fenda palatina por onde se exteriorizava uma massa ocupando a cavidade oral. O terceiro paciente era do sexo masculino e apresentava uma tumoraçäo em dorso nasal. Após a ressecçäo cirúrgica, todas as peças mostravam glioma nasal. Massas congênitas de Linha Média Nasal podem representar uma lesäo de difícil diagnóstico antes do estudo histopatológico, porém näo se deve poupar esforços para fazer o diagnóstico correto, proporcionando assim um prognóstico acurado e uma programaçäo cirúrgica apropriada

Juvenile nasopharyngeal angiofibroma: the routes of invasion.

The juvenile nasopharyngeal angiofibroma has a characteristic growth in all directions from its origin. However, the extensions of the tumor seem to be independent, each one with distinct behavior. The aim of this study is to analyze the preferential direction and routes of JNA growth, as well as its correlation with the patient's age. We analyzed 33 patients without any previous treatment, attempting to the extension and routes of tumor's growth (CT scan), and its correlation with the patient's age. The sphenopalatine foramen region was affected in all cases. From this point, a growth towards several routes with a different rhythm was noted, determining variable configurations to the tumor. The lateral and superior growths were the most frequent. The expansion into the pterygopalatine fossa was very frequent and could involve important anatomical structures, determining higher morbidity. Three sites were invaded through more than one route: pterygoid fossa, middle cranial fossa and maxillary sinus. There was no significant correlation between invasion route and patient's age. However, considering the age, there was a concomitance between tumor development and facial growth by "displacement". We discuss this condition, suggesting an explanation to the tumor invasion and expansion inside the pterygopalatine fossa.