Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 7 uppsatser.

Thesis (Ph. D.)--University of Washington, 1998. / Vita. Includes bibliographical references (leaves [93]-107).

Prescription opioid (PO) abuse is a growing public health concern worldwide as evidenced by an increasing number of opioid-related hospital admissions with a striking lack of research examining the neural basis underlying cognitive symptomatology. Drugs of abuse, through their impact on the dopaminergic system, are thought to disrupt the cognitive network regulating impulse control and incentive salience through inhibition of goal-oriented behaviour and drug-induced attentional biases. The objective of the present study is to examine neurocognitive processes in PO abusers (vs. healthy controls) by relying on the enhanced temporal resolution (1ms) of event-related potentials (ERPs) to track information processing abnormalities associated with cognitive control. In a naturalistic clinical study, 16 patients actively using prescription opioids and 16 healthy controls (matched for age, gender, educational level and smoking status) were assessed using a Go/NoGo and cue reactivity paradigm. Analysis revealed no significant differences in N2 or P3 amplitude, measures of inhibitory control, between groups after successful NoGo trials and no significant differences in ERN or Pe amplitude, measures of error processing, between groups after unsuccessful NoGo trials. Cue reactivity analysis of attention-related ERP components in patients demonstrated significantly (p<0.005) smaller P2 amplitudes, indexing the commencement of attentional processing, for drug pictures compared to neutral and affective pictures. Furthermore, stimulus type did not significantly modulate LPP amplitudes, indexing sustained attention, in patients however arousal ratings for drug pictures were positively correlated with LPP amplitudes in patients. These ERP results of altered cognitive control and incentive salience suggest the neural mechanisms underlying these cognitions are affected by chronic opioid abuse. Investigating the cognitive abnormalities experienced by PO abusers is an important factor in understanding the neural correlates of substance abuse and in predicting successful outcomes to ensure the best chance at long-term recovery for addicted individuals.

Utilizing a social construction perspective, this study uses a mixed method approach to examine the opioid epidemic. The study begins by identifying the numerous claims-making groups along with conducting a content analysis of the rhetoric and symbols used to legitimize the claims about the opioid epidemic. The data for the content analysis was obtained through a search of the websites, newsrooms, and pressrooms of claims-making groups. Additionally, the study examines and assesses the volume of money that is generated and allocated towards opioid research and prevention in an effort to determine who has more power to influence the policy initiatives. Findings show that the frequency of rhetoric and the number of claims-making groups releasing information about the opioid epidemic increased from 2010-2016. Most of the rhetoric consists of groups proposing resolution strategies and formulating new policies. Only a few claims-makers are making financial contributions towards opioid prevention initiatives and in most cases, it is a very small amount of money.

L’utilisation des opioïdes est à l’origine de phénomènes de tolérance et d’hyperalgésie induite (HIO) aussi bien chez l’animal qu’en utilisation clinique. Ces phénomènes surviennent avec tous les opioïdes de manière dose-dépendante. Les mécanismes qui les sous-tendent sont complexes et imparfaitement connus. Le rémifentanil et le sufentanil sont les opioïdes les plus utilisés en France en anesthésie-réanimation. Leur utilisation s’accompagne d’une HIO qui majore la douleur postopératoire et peut être responsable de la persistance de la douleur à long terme. La perception des stimuli nociceptifs chez un patient sous anesthésie générale n’est pas aisée et repose encore sur des signes cliniques indirects d’activation du système sympathique. Ces signes peu sensibles et peu spécifiques conduisent à sous doser ou sur-doser les patients en opioïdes. Récemment, un nouvel outil de monitorage de la nociception est apparu, l’analgesia nociception index (ANI). L’ANI reflète le tonus parasympathique et de ce fait permettrait aux anesthésistes de mieux adapter le dosage des opioïdes. Dans cette thèse, nous avons d’abord évalué la sensibilité et la spécificité de l’ANI à détecter les stimuli nociceptifs, puis montré qu’elles étaient supérieures à celles des signes cliniques, et supérieures à d’autres indices de monitorage proposés. Ensuite nous avons validé la capacité de l’ANI à guider l’analgésie peropératoire du rémifentanil dans différentes situations.Sur le plan expérimental, nous avons exploré, après une exposition courte ou prolongée à différentes doses de rémifentanil et de sufentanil, les mécanismes associés à l’hyperalgésie thermique in vivo, chez la souris, et ex vivo, sur la voie des MAP kinases ERK1/2 et sur le trafic membranaire des récepteurs opioïdes de type µ (MOR) dans différentes cultures cellulaires. Chez la souris, nous avons mis en évidence une hyperalgésie précoce au saut sur plaque chaude, après exposition aux doses les plus élevées de rémifentanil, mais pas avec le sufentanil. De plus, nous n’avons pas observé d’HIO sur le léchage des pattes.Sur les cultures cellulaires, le rémifentanil comme le sufentanil activent la voie des MAPK ERK1/2 lors d’une exposition courte, avec apparition d’une désensibilisation lorsque l’exposition se prolonge. Le rémifentanil comme le sufentanil induisent une internalisation précoce et progressive des récepteurs MOR. / The use of opioids is associated with tolerance and induced hyperalgesia (OIH). Tolerance and OIH occur with all opioids and have been demonstrated both, in animals and in humans and are likely to be dose-dependent. The underlying mechanisms are complex and partially known. Remifentanil and sufentanil are the most used opioids in France in anesthesia and intensive care. Their use is associated with OIH that increases postoperative pain and may be responsible for persistent pain. In anesthetized patients, nociceptive stimuli are still detected according to clinical signs of sympathetic activation. These signs lack sensitivity and specificity and lead to underdosing or overdosing opioids. Recently, the analgesia nociception index (ANI), has been proposed as surrogate marker of nociception. The ANI reflects the parasympathetic tone and thus may allow anesthetists to better adapt the opioid dosage. In this thesis, we first evaluated the sensitivity and specificity of ANI to detect nociceptive stimuli, and showed that it better detects them than do clinical signs or than other currently available monitoring tools. Subsequently, we validated the ability of the ANI to adequately guide the intraoperative dosing of remifentanil in different clinical setting.After acute and sustained exposure to different doses of remifentanil and sufentanil we investigated, in vivo, the mechanisms associated with thermal hyperalgesia in mice, and ex vivo, the effect on the MAP kinase ERK1/2 pathway and the μ-type opioid receptor (MOR) membrane trafficking in human neuroblastoma and embryonic kidney cell cultures. In mice, high-dose remifentanil induced early hyperalgesia assessed by the jumping latency in a hot-plate test, but not the sufentanil. We did not observe OIH for the hind paw licking test. On cell cultures, after short exposure, both remifentanil and sufentanil produced activation of the MAP kinase ERK1/2 pathway, and rapid desensitization and internalization of the MOR.

1. Whole-cell patch recordings were made from substantia gelatinosa (SG) neurons in transverse lumbar spinal cord slices of 15- to 30-day-old rats. 2. Endomorphin 1 (EM-1) or EM-2 (≤ 10 μM) hyperpolarized or induced an outward current in 26 of the 66 SG neurons. The I-V relationship showed that the peptide activates an inwardly rectifying K + current. 3. EM-1 or EM-2 (0.3-10 μM) suppressed short-latency excitatory postsynaptic currents (EPSCs) and long-latency inhibitory postsynaptic currents (IPSCs) in nearly all SG neurons tested or short-latency IPSCs in six of the 10 SG neurons. [Met 5] enkephalin or [D-Ala 2, N-Me-Phe 4, Gly 5-ol]-enkephalin (DAMGO) (1-10 μM) depressed EPSCs and IPSCs. EM-1 or EM-2 depressed synaptic responses without causing a significant change in holding currents or inward currents induced by glutamate. 4. Glutamate also evoked a short-latency outward current in five SG neurons or a biphasic current in two neurons; the outward current was blocked by tetrodotoxin (TTX, 0.3 μM) or bicuculline (10 μM). EM-1 or DAMGO (1 or 5 μM) attenuated the glutamate-evoked outward or biphasic currents in four of the seven SG neurons. 5. EM-1 (1 μM) reduced the frequency, but not the amplitude of miniature EPSCs or miniature IPSCs. 6. Naloxone (1 μM) or the selective μ-opioid receptor antagonist β-funaltrexamine (β-FNA, 25 μM) antagonized the action of EM; EM-induced hyperpolarizations persisted in the presence of the κ-opioid receptor antagonist (nor-binaltorphimine dihydrochloride, 1 μM) and/or σ-opioid receptor antagonist (naltrindole hydrochloride, 1 μM). 7. It may be concluded that EM acting on μ-opioid receptors hyperpolarizes a population of SG neurons by activating an inwardly rectifying K + current, and attenuates excitatory and inhibitory synaptic currents evoked in a population of SG neurons, probably by a presynaptic site of action.

Indiana University-Purdue University Indianapolis (IUPUI) / The aim of this research is to design a new method to identify the opioid use problems (OUP) among long-term opioid therapy patients in Indiana University Health using text mining and machine learning approaches. First, a systematic review was conducted to investigate the current variables, methods, and opioid problem definitions used in the literature. We identified 75 distinct variables in 9 models that majorly used ICD codes to identify the opioid problem (OUP). The review concluded that using ICD codes alone may not be enough to determine the real size of the opioid problem and more effort is needed to adopt other methods to understand the issue. Next, we developed a text mining approach to identify OUP and compared the results with the current conventional method of identifying OUP using ICD-9 codes. Following the institutional review board and an approval from the Regenstrief Institute, structured and unstructured data of 14,298 IUH patients were collected from the Indiana Network for Patient Care. Our text mining approach identified 127 opioid cases compared to 45 cases identified by ICD codes. We concluded that the text mining approach may be used successfully to identify OUP from patients clinical notes. Moreover, we developed a machine learning approach to identify OUP by analyzing patients’ clinical notes. Our model was able to classify positive OUP from clinical notes with a sensitivity of 88% on unseen data. We concluded that the machine learning approach may be used successfully to identify the opioid use problem from patients’ clinical notes. / 2019-06-21

Opioid misuse and addiction constitute a significant public health challenge in the 21st century, with opioids involved in the majority of drug overdose deaths since 1999. A vigorously researched area that contributes substantially to the opioid misuse and addiction challenge is pain. The impact of pain, however, on important health outcomes for individuals in recovery from opioid use is less well understood. The effects of pain on substance use and mental health outcomes was investigated among individuals in recovery from opioid use disorder. Two studies are reported. First, the relationships between pain status and severity on substance use, treatment utilization, and mental health outcomes (e.g., depressive symptoms) was characterized cross-sectionally. Second, subgroups of OUD recovery defined by depression, opioid withdrawal, and pain were identified. Relationships between recovery subgroups, OUD symptoms, remission, opioid use, and quality of life were assessed. Finally, transitions among subgroups across 4 years of recovery were characterized. The present findings support pain as a key dimension of opioid use disorder recovery, highlighting the distinction between acute and chronic pain, the dynamic nature of opioid use disorder recovery, and emphasizing the necessity of integrating pain into opioid use disorder treatment. / Doctor of Philosophy / Misuse of and addiction to opioids is a significant health challenge. Pain has played a central role in facilitating the opioid epidemic in the United States, but the impact of pain on substance use and mental health outcomes for individuals in recovery from opioid use is less well understood. The following two studies investigated how pain affects substance use and mental health outcomes among individuals in recovery from opioid use disorder. Study 1 examined how different types of pain (chronic pain, acute pain, no pain) affect substance use, treatment use, and mental health measures (e.g., depression, quality of life). Study 2 investigated the role that depression, opioid withdrawal, and pain have in defining different groups in opioid recovery. Together these studies support pain as an important factor in OUD recovery, highlight the distinction between acute and chronic pain, emphasize the importance of integrating treatment for opioid use disorder and pain, and demonstrate that opioid use disorder recovery is a dynamic process with individuals transitioning among different recovery groups over time.

America is engulfed in an opioid epidemic. Whether this is depicted through the tens of thousands of lives claimed by the number of drug overdoses each year, the unprecedentedly high and increasing rates of opiate abuse, or the broadening demographic profile of the addict, it is clear that the current issue is one that requires serious attention. As informed by the negative attitudes toward drug addiction that have prevailed since the War on Drugs was declared, it is hypothesized that much of the contemporary predicament is a result of this misinformation that did not resolve, but exacerbated the drug crisis. Despite the concurrent emergence of evidence asserting that addiction is a disease, instead, the idea that drug addiction is a failure prevails. As with many brain diseases, drug addiction displays both pathological alterations in the transmission of signals within the neural circuitries and the morphological defects associated with non-random regions of the brain. The alteration that is observed during opioid tolerance is the desensitization of mu opioid receptors to dopamine, resulting in the need of increased dosage of opiates to achieve the same high. During opioid dependence, key changes that are seen in the locus ceruleus and the mesolimbic reward system increase both the likelihood of an overdose event and withdrawal when an exogenous opioid is present or absent, respectively. There are two models that describe additional changes that occur during the transition from frequent abuse to addiction: (1) the “Changed Set Point Model” and (2) the “Cognitive Deficits Model.” All three variants of the “Changed Set Point Model” portray a shift in the physiological set points of dopamine and glutamate levels in the reward system and regions that control it. The “Cognitive Deficits Model” theorizes that the modifications localized to the prefrontal cortex are responsible for the ultimate transition. Once the abuser is thrust into the addiction cycle, additional changes in the neural networks are observed. These changes are seen in each of the three phases: (1) Binge and Intoxication, (2) Withdrawal and Negative Affect, and (3) Preoccupation and Anticipation. In the first phase, a process called drug-induced neuroplasticity occurs, resulting in the amplification of signals originating from dopaminergic neurons. Next, during Withdrawal and Negative Affect phase, among other changes, the amygdala is shown to be re-wired in such a way that the addict is more sensitive to stress. And finally in the last phase, the changes that occur, secondary to processes similar to drug-induced, are indicated in the prefrontal cortex. The current FDA-approved medication-assisted therapies include methadone, buprenorphine, and naltrexone. The single outstanding abstinence-based treatment is the 12-step program. In the evaluation of medical and non-medical interventions the relative efficacies were measured using the metrics: (1) rates of abstinence achievement, (2) rates of opioid use, and (3) retention in treatment. Individually, all therapies show moderate success when measured against each metric, which further validates the brain disease model for addiction, and also indicates that the future direction of addressing the opioid epidemic should point at combination therapies. What is most imperative now is for there to be more widespread recognition of the brain disease model for addiction.

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