Tesis sobre el tema "Analgesics/opioids"

Thesis (MSc (Hons.)Health) -- University of Western Sydney, Macarthur, 2000.
"March 2000" "A thesis presented to the University of Western Sydney Macarthur in partial fulfilment of the requirements for the Degree of Master of Science (Hons) Health" Bibliography: leaves 90-101.

All clinical opioid analgesics target the MOP (Mu Opioid Peptide) receptor. While these drugs provide analgesia, long-term treatment leads to tolerance and dependence. By targeting MOP and another member of the opioid receptor family, such as DOP (Delta Opioid Peptide receptor) or NOP (Nociceptin Orphanin F/Q Opioid Peptide receptor), these adverse effects are attenuated. Furthermore, solely targeting DOP or NOP may produce analgesia without the adverse effects associated with MOP. Three groups of variably mixed ligands have been developed; i) Fentanyl-based DOP and NOP bivalents, ii) peptide based MOP and NOP bivalents iii) tetrabranched NOP and DOP monovalent ligands. The pharmacology of these ligands has been investigated in a range of intracellular signalling assays. All compounds were tested in Chinese hamster ovary (CHO) cells expressing human MOP, NOP, DOP or KOP (Kappa Opioid Peptide receptor) receptors. Initial work with Fentanyl-based DOP bivalents resulted in a loss of functional activity at the MOP receptor. Further Fentanyl-derivatives conjugated with Ro65-6570 displayed partial agonist activity at MOP and full agonist activity at MOP. A second MOP/NOP bivalent pharmacophore, (DeNO), based on the peptides Dermorphin (MOP) and N/OFQ demonstrated full agonist activity at both receptors. A tetrabranched ligand formed from N/OFQ, displayed increased potency at the NOP receptor compared to N/OFQ. DeNO was investigated in human embryo kidney (HEK) cells which co-expressed MOP and NOP. The results of functional assays demonstrated a loss of MOP activity caused by the presence of NOP. Further studies with the opioids, Dermorphin and N/OFQ, and antagonists naloxone (MOP) and UFP-101(NOP), have demonstrated a structural interaction between MOP and NOP in this cell line. The work in this thesis demonstrates how modification of peptide structures was more successful in the development of multitarget ligands. The findings from this thesis provide a significant contribution to theory of receptor heterodimerisation between MOP and NOP, as demonstrated by the loss of potency of MOP agonists in the co-expression system.

Efter operation och anestesi får patienter ofta en negativ påverkan på magsäck och tarmar. Illamående och kräkningar är ett stort problem och många har svårt att komma igång med intag av föda och normal tarmfunktion då magsäcken och tarmarna ”står stilla”. Flera faktorer bidrar- bl.a. smärtan, det kirurgiska traumat och de läkemedel vi ger i samband med anestesin. Av de senare är opioider, d.v.s morfin och morfinliknande läkemedel, starkt bidragande. I detta avhandlings- arbete har opioiders effekter på magsäckens motilitet studerats. Med ett absorptionstest (paracetamolmetoden) studerades hos frivilliga hur opioiden remifentanil påverkar magsäckstömning och om kroppspositionen har betydelse för tömningshastigheten ut i tarmen. Remifentanil fördröjde magsäcks-tömningen och under pågående opioid behandling hade kroppspositionen ingen större betydelse, vilket det däremot hade under kontrollförsöken. Med samma metod jämförde vi hos patienter två anestesimetoder och studerade magsäcks-tömning direkt efter en operation. Ingen skillnad kunde påvisas mellan en opioidbaserad och en opioidfri anestesi, men inom respektive grupp var det en stor variation i magsäckstömning mellan individerna. Med en barostat studerades tonus i övre delen av magsäcken. Hos hälften av de frivilliga orsakade remifentanil en ökning av tonus och hos den andra hälften en minskning av tonus. Vidare undersöktes hos en grupp patienter opioiden fentanyls påverkan på den elektriska aktiviteten i magsäcken. Med en elekroga-strograf (EGG) registrerades de långsamma elektriska vågor som koordinerar muskelrörelserna i magsäcken. Hos hälften av de undersökta påverkades aktiviteten av fentanyl med en sänkt vågfrekvens eller upphörande av vågor, medan aktiviteten var opåverkad hos den övriga hälften. För att finna en förklaring till variationen gjordes genetiska analyser av genen för opioidreceptorn hos de undersökta i barostat och EGG studierna. Variationer i genomet, s.k. polymorfism, var inte associerad till utfallen i studierna. Studierna har visat på att opioider har en uttalad effekt på magsäckens motilitet och att den varierar kraftigt mellan individer. Polymorfism i genen för opioid- receptorn förklarade inte skillnaden mellan individer. Direkt efter operation bidrar sannolikt andra faktorer än anestesimetod till det variabla utfallet i magsäckstömning.
After anesthesia and/or surgical procedures, gastrointestinal motility is commonly impaired. The causes are multifactorial, with surgical trauma, pain and perioperative drugs playing a major role. This thesis explores opioid effects on gastric motility in healthy volunteers and patients undergoing surgery. Gastric emptying was studied by an absorption test (paracetamol method), and in healthy volunteers a remifentanil infusion delayed gastric emptying. Body position altered emptying during the control situations, but not during the remifentanil infusion. Further, two anesthetic methods were compared and no differences were found in immediate postoperative gastric emptying between a remifentanil/propofol based intravenous anesthesia and an opioid free inhalational anesthesia, although the interindividual variability was high. Proximal gastric tone was studied using a gastric barostat. An infusion of remifentanil caused two patterns of reaction regarding gastric tone, with half of the subjects increasing and half decreasing in gastric tone. Gastric myoelectrical activity was evaluated with electrogastrography (EGG), and a bolus dose of fentanyl caused a decrease in frequency of the gastric slow waves or disrupted this activity. However, the activity was unaffected in half of the investigated subjects. Analysis of polymorphisms (A118G and G691C) in the µ-opioid receptor gene was performed to find an explanation for the great interindividual variations seen in the barostat and EGG studies, but no association could be found. These studies have shown that opioids have pronounced effects on gastric motility with variable individual responses that are difficult to predict. Polymorphisms in the µ-opioid receptor gene could not explain the variations. Postoperatively, other factors might contribute more than opioids to the impairment in gastric motility.
ISSN 1652-4063

Notre recherche concerne les conditions d'acceptabilité de différents moyens de traiter la douleur dans les soins palliatifs, par les professionnels de santé et le grand public. Deux moyens sont étudiés : l’utilisation d’antalgiques, notamment de palier III ; la mise en œuvre d’une sédation. Notre recherche est basée sur la Théorie Fonctionnelle de la cognition de Norman Anderson (1981). Concernant l'étude portant sur l’utilisation des antalgiques : 192 participants ont jugé du degré d'acceptabilité de chacun des 56 scénarios proposés, résultant de la combinaison de quatre facteurs : « concertation du médecin avec l’équipe de soins », « demande de la personne à être soulagée de sa douleur », « niveau de douleur, exprimé grâce à l’échelle numérique de douleur », « décision du médecin en termes de prescription d’antalgique ». Pour l'étude portant sur la sédation : 192 personnes ont jugé du degré d'acceptabilité des 48 scénarios proposés. Ils sont le résultat de la combinaison des quatre facteurs suivants : « demande de la personne », « type de sédation », « espérance de vie », « concertation du médecin avec l’équipe de soins ». Pour l’étude portant sur l’utilisation des antalgiques, notamment de palier III, il ressort que seuls trois des facteurs manipulés ont joué un rôle dans l’acceptabilité de la décision du médecin. Il s’agit par ordre croissant des facteurs « niveau de douleur », « décision du médecin » et « concertation du médecin ». Le facteur le moins influent puisque n’ayant pas eu d’effet significatif est le facteur « demande de la personne ». L’analyse en clusters nous a également permis de discriminer 6 groupes de participants, ayant chacun leur propre politique de jugement. Concernant l’étude sur la sédation, nous retrouvons également que trois des quatre facteurs manipulés ont eu une influence sur le jugement d’acceptabilité. Par ordre croissant, il s’agit des facteurs « demande de la personne », « type de sédation » et « concertation du médecin ». Le facteur « espérance de vie » n’a pas eu d’effet significatif. L’analyse en clusters nous a permis de différencier 4 classes de participants, se regroupant selon leur politique de jugement. L'acceptabilité des différents moyens utilisés pour soulager la douleur en fin de vie est largement influencée par les facteurs intervenant dans les scénarios
Our research concerns the conditions of acceptance of different ways to treat pain in palliative care by health professionals and laypeople. Two ways are studied: the use of analgesic, including strong opioids ; implementation of sedation. Our research is based on the Functional Theory of Cognition by Norman Anderson (1981). On the study on the use of analgesics : 192 participants rated the degree of acceptability of each of the 56 proposed scenarios, resulting from the combination of four factors: « decision-making process », « request of the person to be relieved of his pain », « pain level, expressed through digital pain scale », « decision of the physician in terms of painkiller prescription ». For the study of sedation : 192 people judged the acceptability of the 48 proposed scenarios. They are the result of four factors combination: « request for sedation », « type of sedation », « life expectancy », « decision-making process ». In the study on the use of painkillers, especially strong opioids, it appears that only three of the manipulated factors played a role in the acceptability of the doctor's decision. The result by ascending order of the factors is: « pain level », « decision » and « decision-making process ». The less influential factor, since having no significant effect, is the factor « request ». The analysis in clusters also allowed us to discriminate 6 groups of participants, each with their own political judgment. Regarding the study on sedation, we also find that three of the four manipulated factors had influenced the judgment of acceptability. In ascending order, these factors are « request », « type of sedation » and « decision-making process ». The « life expectancy » factor had no significant effect. The analysis in clusters enabled us to distinguish 4 classes of participants, coming together according to their political judgment. The acceptability of the various means used to relieve pain in later life is largely influenced by the factors involved in the scenarios

Embora existam muitos estudos clínicos avaliando analgésicos e o controle da dor em cães, poucos são realizados em animais com dor do câncer e submetidos a procedimento cirúrgico para ressecção da neoplasia como a maxilectomia e mandibulectomia. Este estudo clínico foi realizado de forma prospectiva, comparativa, aleatória e de maneira simples cego com o propósito de avaliar a eficácia analgésica de diferentes tratamentos no período pós-operatório em cães submetidos à maxilectomia ou mandibulectomia. Foram utilizados no estudo 42 cães com neoplasia oral. Todos os animais foram prémedicados com acepromazina (0,05mg/kg) associado à meperidina (2mg/kg) por via intramuscular e a anestesia foi induzida com propofol por via iv na dose suficiente realizar a intubação (2.3-6.5mg/kg). O isoflurano foi utilizado para a manutenção da anestesia. Trinta minutos antes do fim do procedimento cirúrgico, os cães foram distribuídos aleatoriamente em um dos 5 diferentes grupos para analgesia pósoperatória: tramadol 2mg/kg (Tra), codeína 2mg/kg (Co), cetoprofeno 2mg/kg (Ce), tramadol 2mg/kg associado ao cetoprofeno 2mg/kg (TraCe) ou codeína 2mg/kg associado ao cetoprofeno 2mg/kg (CoCe), por via subcutânea. A freqüência cardíaca (FC) e respiratória (FR), pressão arterial sistólica (PAS), pressão arterial diastólica (PAD) e pressão arterial média (PAM), glicose sanguínea, cortisol e interleucina-6 (IL- 6) e grau de sedação foram verificados até 24 horas, e grau de analgesia foi verificado por até 120 horas do início da administração do analgésico, ou seja, os respectivos tratamentos foram mantidos por 5 dias da seguinte forma: tramadol ou codeína a cada 8 horas e cetoprofeno a cada 24 horas por via oral (MBL, M1, M2, M3, M4, M5, M24, M48, M72, M96 e M120). O resgate analgésico foi realizado nos animais que apresentaram escore de dor 4 em qualquer momento do estudo (dipirona 25mg/kg e morfina 0,1mg/kg). A análise estatística foi realizada por meio do Kruskal-Wallis, Friedman para mensurações repetidas, ANOVA e teste 2. Os gráficos em boxplot ou diagrama em caixas representam a distribuição dos dados. Os valores com p<0,05 foram considerados significantes. Não houve diferença entre os grupos de tratamento com relação ao peso, tempo de cirurgia, tempo para extubação, FC, FR, PAS, PAD e PAM, cortisol e IL-6 séricos, e escore de dor pela escala de análise descritiva. A concentração da glicose sanguínea aumentou de forma significante com relação aos valores basais no grupo Tra (M5= 96±14), Co (M1= 120±66 e M3=96±21), Ce (M5= 105±22) e CoCe (M3=104±16). Aumento do escore de dor foi observado no M2 do grupo Tra em relação a MBL e M1 a M5 do grupo Co em relação a M120 (p<0,05), contudo a média do escore não foi maior que 2,7. Baixo grau de sedação ainda foi observado no grupo CoCe no M24 (0,1±0,4 p<0,001) com relação ao M1. O número de resgate foi baixo, totalizando 19 administrações. No grupo Ce houve maior necessidade de resgate analgésico. Com base nos resultados obtidos, pôde-se concluir que os grupos de tratamento analgésico promoveram controle da dor pós-operatória de boa qualidade na maioria dos cães do estudo e com baixa incidência de efeitos adversos, podendo ser indicados no controle da dor em procedimentos de maxilectomia e mandibulectomia.
Although there are many clinical studies evaluating analgesics and pain control in dogs, very few were carried out in animals with cancer pain, and submitted to oncologic surgery with tumor resections such as maxillectomy and mandibulectomy. This clinical, prospective, randomized, simple blinded study was performed with the purpose of evaluating analgesic efficacy of different treatments in the postoperative period in dogs submitted to maxillectomy or mandibulectomy. Forty-two client-owned dogs with oral tumor were used in the study. Dogs were premedicated with acepromazine (0.05mg kg-1) and meperidine (2mg kg-1) by the intramuscular route and anesthesia was induced with intravenous propofol in a dose sufficient to allow intubation (2.3-6.5mg-1). Isoflurane was used for maintenance of anesthesia. Thirty minutes prior to the end of surgery, dogs were randomly allocated in one of 5 different groups for postoperative analgesia: tramadol 2mg kg-1 (Tra), codeine 2mg kg-1 (Co), ketoprofen 2mg kg-1 (Ke), tramadol 2mg kg-1 + ketoprofen 2mg kg-1 (TraKe) or codeine 2mg kg-1 + ketoprofen 2mg kg-1 (CoKe), subcutaneously. Heart (HR) and respiratory (RR) rates, systolic (SBP), median (MBP) and diastolic (DBP) blood pressures, blood glucose, serum cortisol and interleukin-6 (IL-6) and degree of sedation were recorded for 24 hours, and degree of analgesia were evaluated until 120 hours of the start of analgesic administration (MBL, M1, M2, M3, M4, M5, M24, M48, M72, M96 and M120), being that treatments were maintained for 5 days as follows: codeine or tramadol every 8 hours and the ketoprofen every 24 hours orally. Analgesic rescue was delivered to animals with pain scores equal or superior to 4 at any time of the study (dypirone 25mg -1 and morphine 0,1mg-1). Statistical analyses were performed by means of the Kruskal-Wallis, Friedmann for repeated measures, ANOVA and 2 tests. Graphics boxplot or box diagrams represents dates of distribution. Values of p<0.05 were considered significant. There were no differences between groups related to weight, surgical time, extubation time, HR, RR, SBP, MBP, DBP, serum cortisol and IL-6, and pain score by Descriptive Scale (DS). Blood glucose concentrations were significantly increased in relation to baseline, in groups Tra (M5= 96±14), Co (M1= 120±66 e M3=96±21), Ke (M5= 105±22) and CoKe (M3=104±16). Increase of pain score was observed in M2 of group Tra in relation to baseline, and M1 to M5 of group Co in relation to M120 (p<0,05), however the average score was not higher than 2.7. Low level of sedation was also observed in group CoKe in M24 (0.1 ± 0.4 - p <0.001) compared to M1.. The number of rescue was low, totaling 19 administrations. Ke group required more analgesic rescue. So, it can be conclude that treatment analgesic groups promoted a good quality pain control of postoperative in most of the dogs in the study and with low incidence of side effects, could be indicated in the control of the pain in procedures of maxillectomy and mandibulectomy.

La douleur est un problème majeur chez les personnes diagnostiquées d’un cancer. Elle est souvent sous-déclarée, sous-évaluée et sous-traitée. Cette thèse vise, à travers deux approches quantitative et qualitative, à enrichir le corpus de connaissances sur la problématique du sous-traitement de la douleur chez les personnes atteintes d’un cancer et à explorer le rôle des déterminants sociaux et médicaux dans l’accès aux opioïdes. Les résultats montrent une prévalence de la douleur toujours élevée, même 5 ans après un diagnostic, sans doute en raison d’un sous-traitement par les opioïdes. Ils montrent aussi des associations significatives entre le profil sociodémographique et médical des patients et l’accès aux opioïdes et aux soins palliatifs. Nos résultats suggèrent donc la nécessité de prendre en compte le caractère complexe et multidimensionnel de la douleur ainsi que le profil des patients afin d’assurer une prise en charge globale, multidisciplinaire et équitable
Pain is a major problem in people with cancer. It is often under-reported, under-assessed and under-treated. This thesis aims, through two quantitative and qualitative approaches, to enrich the body of knowledge on the problem of undertreatment of pain in people with cancer and to explore the role of social and medical determinants in access to opioids. The results show a still high prevalence of pain, even 5 years after diagnosis, probably due to an undertreatment by opioids. They also show significant associations between patients’ socio-demographic and medical profile and access to opioids and palliative care. Our results therefore suggest the need to take into account the multidimensional nature of pain as well as the profile of patients in order to ensure comprehensive, multidisciplinary and equitable care

Lifetime prevalence estimates of psychotropic medicine use as well as prevalence of DSM-IV prescription drug use disorders from the baseline investigation of the Early Developmental Stages of Psychopathology (EDSP) Study are presented. Use of prescription medication at some time in their life was reported by 27.4% of the respondents. Illicit use of prescription drugs, which means an intake without medical legitimation, was reported by 4.5% of the sample. The findings suggest that abuse of and dependence on prescription drugs, with most cases reporting polysubstance use, is quite rare in the 14- to 24-year-olds. DSM-IV abuse was more prevalent than dependence (0.5 vs. 0.3%). In general, women reported higher prevalence rates of prescription drug use, whereas men reported higher prevalence rates of prescription drug disorders. This result suggests that men have a higher risk to develop a substance-use-related disorder.

Opioid addiction has reached an all-time high in America, partially because there is no federally approved, affordable, available alternative for chronic pain. This paper examines the role of medical cannabis in the opioid crisis by exploring the effect of medical cannabis laws on opioid prescription rates in an OLS regression. I found that medical cannabis laws produce a statistically significant decrease in opioid prescription rates. I discuss the specific policy components that would allow medical cannabis policy to be most effective nationwide.

Lifetime prevalence estimates of psychotropic medicine use as well as prevalence of DSM-IV prescription drug use disorders from the baseline investigation of the Early Developmental Stages of Psychopathology (EDSP) Study are presented. Use of prescription medication at some time in their life was reported by 27.4% of the respondents. Illicit use of prescription drugs, which means an intake without medical legitimation, was reported by 4.5% of the sample. The findings suggest that abuse of and dependence on prescription drugs, with most cases reporting polysubstance use, is quite rare in the 14- to 24-year-olds. DSM-IV abuse was more prevalent than dependence (0.5 vs. 0.3%). In general, women reported higher prevalence rates of prescription drug use, whereas men reported higher prevalence rates of prescription drug disorders. This result suggests that men have a higher risk to develop a substance-use-related disorder.

Nursing homes are an essential yet understudied provider of cancer-related care for those with complex health needs. Nine percent of nursing home residents have a cancer diagnosis at admission, and it is estimated that one-third of them experience pain on a daily basis. Although pain management is an essential component of disease treatment, few studies have evaluated analgesic medication use among adults with cancer in this setting. Use of opioids, which are the mainstay of pain management in older adults because of their effectiveness in controlling moderate to severe pain, may be significantly related to coverage by the Medicare Part D prescription drug benefit. However, little is known about Medicare Part D’s effects on opioid use in this patient population. A limited body of evidence also suggests that despite known risks of overdose and respiratory depression in opioid-naïve patients treated with long-acting opioids, use of these agents may be common in nursing homes. This dissertation examined access to appropriate and effective pain-related health care services among US nursing home residents, with a special focus on those with cancer. Objectives of this dissertation were to: 1) estimate the prevalence, and identify resident-level correlates, of pain and receipt of analgesic medications; 2) use a quasi-experimental research design to examine the relationship between implementation of Medicare Part D and changes in the use of fentanyl patches and other opioids; and 3) to estimate the prevalence, and identify resident-level correlates, of naïve initiation of long-acting opioids. Data on residents’ health status from the Resident Assessment Instrument/Minimum Data Set (versions 2.0 and 3.0) were linked with prescription drug transaction data from a nationwide long-term care pharmacy (January 2005–June 2007) and the Centers for Medicare and Medicaid Services (January–December 2011). From 2006 to 2007, more than 65% of residents of nursing homes throughout the US with cancer experienced pain (28.3% on a daily basis), among whom 13.5% reported severe pain. More than 17% of these residents who experienced daily pain received no analgesics (95% confidence interval [CI]: 16.0–19.1%), and treatment was negatively associated among those with advanced age, cognitive impairment, feeding tubes, and restraints. These findings coincided with changing patterns in opioid use among residents with cancer, including relatively abrupt 10% and 21% decreases in use of fentanyl patches and other strong opioids, respectively, after the 2006 implementation of Medicare Part D. In the years since Medicare Part D was introduced, some treatment practices in nursing homes have not been concordant with clinical guidelines for pain management among older adults. Among a contemporary population of long-stay nursing home residents with and without cancer, 10.0% (95% CI: 9.4–10.6%) of those who began receiving a long-acting opioid after nursing home admission had not previously received opioid therapy. Odds of naïve initiation of these potent opioids were increased among residents with terminal prognosis, functional impairment, feeding tubes, and cancer. This dissertation provides new evidence on pharmaceutical management of pain and on Medicare Part D’s impact on opioid use in nursing home residents. Results from this dissertation shed light on nursing home residents’ access to pain-related health care services and provide initial directions for targeted efforts to improve the quality of pain treatment in nursing homes.

Nursing homes are an essential yet understudied provider of cancer-related care for those with complex health needs. Nine percent of nursing home residents have a cancer diagnosis at admission, and it is estimated that one-third of them experience pain on a daily basis. Although pain management is an essential component of disease treatment, few studies have evaluated analgesic medication use among adults with cancer in this setting. Use of opioids, which are the mainstay of pain management in older adults because of their effectiveness in controlling moderate to severe pain, may be significantly related to coverage by the Medicare Part D prescription drug benefit. However, little is known about Medicare Part D’s effects on opioid use in this patient population. A limited body of evidence also suggests that despite known risks of overdose and respiratory depression in opioid-naïve patients treated with long-acting opioids, use of these agents may be common in nursing homes. This dissertation examined access to appropriate and effective pain-related health care services among US nursing home residents, with a special focus on those with cancer. Objectives of this dissertation were to: 1) estimate the prevalence, and identify resident-level correlates, of pain and receipt of analgesic medications; 2) use a quasi-experimental research design to examine the relationship between implementation of Medicare Part D and changes in the use of fentanyl patches and other opioids; and 3) to estimate the prevalence, and identify resident-level correlates, of naïve initiation of long-acting opioids. Data on residents’ health status from the Resident Assessment Instrument/Minimum Data Set (versions 2.0 and 3.0) were linked with prescription drug transaction data from a nationwide long-term care pharmacy (January 2005–June 2007) and the Centers for Medicare and Medicaid Services (January–December 2011). From 2006 to 2007, more than 65% of residents of nursing homes throughout the US with cancer experienced pain (28.3% on a daily basis), among whom 13.5% reported severe pain. More than 17% of these residents who experienced daily pain received no analgesics (95% confidence interval [CI]: 16.0–19.1%), and treatment was negatively associated among those with advanced age, cognitive impairment, feeding tubes, and restraints. These findings coincided with changing patterns in opioid use among residents with cancer, including relatively abrupt 10% and 21% decreases in use of fentanyl patches and other strong opioids, respectively, after the 2006 implementation of Medicare Part D. In the years since Medicare Part D was introduced, some treatment practices in nursing homes have not been concordant with clinical guidelines for pain management among older adults. Among a contemporary population of long-stay nursing home residents with and without cancer, 10.0% (95% CI: 9.4–10.6%) of those who began receiving a long-acting opioid after nursing home admission had not previously received opioid therapy. Odds of naïve initiation of these potent opioids were increased among residents with terminal prognosis, functional impairment, feeding tubes, and cancer. This dissertation provides new evidence on pharmaceutical management of pain and on Medicare Part D’s impact on opioid use in nursing home residents. Results from this dissertation shed light on nursing home residents’ access to pain-related health care services and provide initial directions for targeted efforts to improve the quality of pain treatment in nursing homes.

Die schmerzstillende Wirkung von Opiaten wird über Opioidrezeptoren im zentralen und peripheren Nervensystem vermittelt. Die Schmerzlinderung kann jedoch mit sehr starken Nebenwirkungen einhergehen, die das Patientenwohlbefinden beeinträchtigen. Dies legt die Bedeutung von neuen Opioidanalgetika nahe, die ihre schmerzstillende Wirkung ausschließlich über Opioidrezeptoren im PNS entfalten, ohne unerwünschte zentrale Nebenwirkungen zu induzieren. Die orale Gabe von Medikamenten minimiert Unannehmlichkeiten für den Patienten, jedoch müssen die Substanzen die intestinale Barriere passieren können, um in die Blutzirkulation eintreten zu können. Die intestinale Permeabilität von zwei peripher wirksamen Opiaten (AS006 und Loperamid) wurde in Ussing-Kammer Experimenten untersucht. Um die Darmepithelpermeabilität für beide Opiate zu erhöhen, wurde der Absorptionsverstärker Chitosan verwendet. Chitosan bewirkte nach 30 Minuten bei HT29/B6 und Caco-2 Zelllinien eine Abnahme des epithelialen Widerstands in vitro. Die Permeabilität für AS006 war bei beiden Zelllinien erhöht, für Loperamid nur bei HT29/B6, jedoch nicht bei Caco-2 Zellmonolayern. Verhaltensexperimente zur Messung des antinozizeptiven Effektes von oral appliziertem Loperamid auf Entzündungsschmerz wurden an Ratten durchgeführt. Die orale Gabe von Loperamid induzierte eine Dosis-abhängige antinozizeptive Wirkung in der entzündeten Hinterpfote. Bei oraler Gabe von Loperamid in Kombination mit Chitosan wurde keine signifikante Verstärkung des maximalen antinozizeptiven Effekts von Loperamid beobachtet. Zusammenfassend ist Chitosan ein geeigneter Absorptionsverstärker für intestinale Permeabilitätsstudien von peripher wirksamen Opioidanalgetika in vitro. Die in vitro Ergebnisse haben gezeigt, dass der Effekt von Chitosan auf Loperamid möglicherweise schwächer ist als auf AS006. Dementsprechend fiel die Wirkung des Absorptionsverstärkers auf Loperamid-induzierte Analgesie im Verhaltensversuch eher gering aus.
Analgesic effects of opioids are mediated by opioid receptors that are widely distributed in the central and peripheral nervous systems (CNS and PNS, respectively). Although opioids are the most powerful analgesics, severe side effects restrict their use and affect patient convalescence. This suggests an advantage of new analgesic opioids which selectively bind to opioid receptors in the PNS. After oral administration however, peripherally restricted opioids first have to cross the intestinal epithelial barrier before absorption into the circulation and distribution to opioid receptors in peripheral tissues. Here, the transport across intestinal epithelia of two opioid ligands (AS006 and loperamide) that selectively activate peripheral opioid receptors without entering the CNS were investigated. To increase the intestinal passage of these drugs, the absorption enhancer chitosan was used. Chitosan significantly decreased the transepithelial resistance of HT29/B6 and Caco-2 cell monolayers after 30 min in vitro. The permeability values for AS006 increased from < 0.3 × 10-6 cm/s up to 10 × 10-6 cm/s in the presence of chitosan. In contrast, HT29/B6 monolayers showed moderate loperamide permeability in the presence of chitosan, and chitosan had no effect on the permeability of loperamide using Caco-2 monolayers. Oral administration of loperamide induced a dose-depended elevation of paw pressure thresholds in inflamed paws that lasted for 60 min. Oral administration of loperamide combined with chitosan slightly but nonsignificantly enhanced the antinociceptive effect of loperamide. In conclusion, chitosan is a suitable absorption enhancer for in vitro intestinal permeability studies. Future in vivo experiments might investigate different formulations and application schedules, and further address the effects of chitosan on the antinociceptive efficacy of hydrophilic opioids.

In the United States, prescription opioids have been a major problem that contributed to the opioid crisis in the country. As dentists prescribe analgesics routinely for dental pain management, further investigation into opioid and non-opioid prescription patterns by dentists on a national level is needed. This research project aimed to examine 1) the trends in opioid and non-opioid analgesic prescriptions by dentists in the US,2) to examine the racial-ethnic disparities in receiving an opioid and non-opioid prescription from a dental professional, 3) the effect of federal Rescheduling of hydrocodone combination on opioid prescription patterns by dentists in a school setting. Data on analgesic prescriptions by dentists were obtained using medical panel survey MEPS (1996- 2015), and Boston University Henry M. Goldman School of Dental Medicine clinical repository (2010 -2019). On average about 31,206 individuals of all ages were interviewed for MEPS each year. The trend in analgesics prescription was reported weighted numbers and proportions of total and dental analgesics prescriptions were reported. Kendall tau correlation test was used to examine trends in the rate of opioid prescriptions per 100 persons over survey years. Racial differences were examined using MEPS data (2002-2015) on dental analgesic prescriptions, dental care utilization, patients’ race, and other demographic information. The outcome was analgesic prescription received. The main independent variable was the patients’ race/ethnicity. Covariates included in the analysis were gender, age, marital status, income, geographical region, and survey year. Using BUSDM data (2010-2019) we examined 12,807 patients who received an opioid prescription from a dentist. The primary outcome variables were opioid prescriptions and opioid morphine milligram equivalent (MME). The primary predictor used is the date of opioid prescription (Time before and after the intervention). To assess the effect of hydrocodone medication reclassification on the outcome variables we used an interrupted time series (ITS) analysis with a segmented regression model. Our results showed a decrease in the proportion of dental opioids out of total opioids from 9.76% in 1996 to 4.5% in 2015. Kendall tau correlation indicated an increase in prescribing rate over the years in total opioids but not in dental opioids. Racial differences were found in opioid prescriptions by dentists with whites having a lower risk of receiving an opioid analgesic compared to other racial minorities. The effect of federal rescheduling of hydrocodone combination on opioid prescription patterns by dentists showed specifically a reduction in non-hydrocodone opioids prescribing rate by morphine milligram equivalent (MME). In conclusion dentists’ contribution to the increase in prescription opioids in the United States seem to be limited compared to other health care professionals. Nevertheless, racial differences were found in whites when compared to other racial minorities. Efforts to curb the use of opioids should be encouraged even more so with evidence supporting the effectiveness of non-opioids analgesics in control of dental pain.
2022-12-09T00:00:00Z