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Context Chronic pain and opioid dependence confer substantial individual and societal burdens and are notoriously difficult to treat effectively. Their comorbid presentation further complicates effective treatment through complex physiological and environmental interactions. Objectives (1) What are the clinical characteristics and treatment outcomes associated with comorbid chronic pain in ORT patients? (2) Does the patient-attributed direction of the causal relationship in the development of opioid dependence and chronic pain identify two clinically-distinct treatment populations? (3) What is the incidence of iatrogenic opioid dependence or abuse following opioid analgesic treatment? (4) Is there evidence of opioid-induced hyperalgesia in humans? Methods Primary data Participants were 467 treatment-seeking, opioid-dependent patients. Materials comprised standardised instruments – focusing on illicit substance use and mental health characteristics – completed by medical staff at study inception, and extracts of routinely-collected clinical datasets spanning the follow-up period. Procedures involved the use of a health informatics approach. Electronic linkage of data collected at study inception with routinely-collected clinical datasets spanning the 5-year follow-up period. Secondary data Systematic searches were undertaken using six electronic research databases, supplemented by manual searches. Study quality was assessed using instruments developed by NIH. Data synthesis using random effects models (DerSimonian-Laird method) generated: (1) a pooled incidence of iatrogenic dependence or abuse following opioid analgesic treatment; and (2) a pooled effect of opioid exposure on the development of opioid-induced hyperalgesia. Additional analyses included assessment of heterogeneity in study effects, within- and between-study risk of bias and sensitivity analyses. Results A total of 246 (53%) patients reported comorbid chronic pain. This ‘comorbid’ group was associated with increased mortality, physical and mental health problems, service utilisation and illicit drug use, specifically benzodiazepines and cannabinoids. Within the ‘comorbid’ group, patients who reported a causal impact of opioid dependence on the development of pain were associated with increased illicit drug use and psychiatric morbidity. Secondary data analyses revealed a 4.7% incidence estimate of iatrogenic dependence or abuse following opioid analgesic treatment, and evidence of the development of opioid-induced hyperalgesia following therapeutic opioid exposure. Conclusions Elevated mortality, morbidity and illicit drug use in opioid-dependent patients with comorbid chronic pain reflects a patient population with substantial health burdens. The dynamic relationship between these severe and chronic conditions necessitates complex, multimodal treatment strategies and multiagency collaboration, including general psychiatric intervention. Whilst a substantial proportion reported that opioid dependence developed as a consequence of pain problems, there is evidence to suggest that the assumed risk of iatrogenic opioid dependence and abuse may be an overestimate; however, therapeutic opioids may lead to other problems that impact on treatment effectiveness, such as opioid-induced hyperalgesia.

The stilbene structure is part of many biologically active natural products, and these compounds can be attractive targets for chemical synthesis. A convergent synthetic design can be utilized in order to install the central olefinic moiety by way of organophosphorus compounds. This design has been employed to prepare a number of natural products, including the potent anti-cancer compounds known as the schweinfurthins and many analogues thereof. Not only do all these structures consist of a stilbenoid scaffold, but all are partially terpenoid in nature as well. Striking similarities to the schweinfurthins would become apparent following the isolation of a new group of compounds, which would later become known as the pawhuskins. In 2004, Belofsky and co-workers reported a small set of prenylated stilbenes that they named pawhuskins. Pawhuskins A-C were isolated from the common North American purple prairie clover (Dalea purpurea) collected near Pawhuska, Oklahoma. Belofsky's findings support an ethnomedical use, because the pawhuskins were shown to modulate opioid receptors through displacement of a nonselective radioactive antagonist (3[H]-naloxone) striatal tissue taken from rat brain. Pawhuskin A was the most potent member of the family, making it one of a small group of compounds that does not contain a basic nitrogen atom but that still exhibits effects on the opiate receptor system. This activity is surprising given the absence of the traditional pharmacophore, a 6-membered piperidine ring containing a basic nitrogen. In these studies, we will report the opioid receptor binding affinity and selectivity of pawhuskin A using a functional assay based on [35S]GTP-γ-S binding. Because of our well-established history of synthesizing prenylated stilbenes, and the unique biological activity of the pawhuskins, we embarked on a synthetic effort targeted at pawhuskin analogues. The preparation of sixteen analogues will be presented. The structure-activity relationship studies of twenty compounds correlated to illuminate more information on the novel pawhuskin pharmacophore will also be reported. Efforts toward preparation of more water-soluble structures similar to the pawhuskins will also be described. The interrelated studies involving pawhuskin analogue synthesis and elucidation of the novel pharmacophore, as well as interesting chemical findings, will be discussed in detail.

Pain management is a critical part of the care of the surgical patient. This study sought to investigate the impact of cultural and linguistic diversity on analgesic administration practices and opioid consumption during postoperative period. A retrospective medical record audit of 278 English-speaking and non-English speaking surgical patients was carried out at four hospitals in Sydney's South West. No differences were found in the type of analgesia prescribed, the mode of analgesia, or the commencement of oral analgesia between the two groups. However, non-English speaking patients consumed less analgesia during the initial postoperative period than their English speaking counterparts. The importance of this difference was further examined within the context of a range of factors known to influence analgesia consumption. A model including sociodemographic and clinical factors - mode of administration of analgesia, gender, and language spoken -predicted 37% of total opioid consumption. Although mode of administration was the most important factor, being of non-English speaking background also contributed substantially. Pain assessment, inclusive of gender and cultural nuances is recommended. The need for further research into pain interpretation in specific linguistic and cultural groups is highlighted / Master of Science (Hons) (Health)

Graduation date: 1998

Graduation date: 1995

The purpose of this study was to elucidate relationships among habitual physical activity level, endogenous opioid level, postoperative opioid analgesic, and experiences of acute pain in response to the noxious stimulation of a subsequent orthopedic surgical procedure. Specifically, the study examined (1) the relationship between habitual activity and preoperative level of endogenous opioids in peripheral blood, and (2) whether habitual activity predicts perception of pain intensity or distress in response to a subsequent noxious stimulus. The study utilized a descriptive correlational design with causal modeling methodology to assess a five-stage theory. The convenience sample was comprised of 36 English-speaking adult subjects hospitalized for orthopedic surgeries. The theoretical concepts, acute pain intensity and distress, were indexed three times for each subject by visual analogue scales. Reliability and validity of the scales were assessed by correlation with concurrent pain measurements using randomized verbal descriptor lists. Multiple regression statistical techniques were used to estimate the theory; violations of causal modeling and statistical assumptions were assessed by residual analysis. For this sample, the strongest predictors of postoperative pain were the immediately preceding comparable indices of pain intensity or pain distress. Approximately 31% of the variance on postoperative analgesic was predicted by the combined effects of immediate postoperative pain and habitual activity. Although activity was not significantly related to endogenous opioid level in peripheral plasma, activity directly and positively influenced immediate postoperative pain intensity (Beta = .37), 24-hour pain distress (B = .27), and total opioid analgesic received in the initial 24 postoperative hours (Intensity B = .40; Distress B = .50). Endogenous opioid was significantly related only to immediate postoperative pain distress (B = -.26). More physically active patients reported greater immediate postoperative pain intensity and greater 24-hour pain distress; they received more postoperative exogenous analgesic. Incorporation of information about activity as a potential determinant of operative pain experiences would increase validity of nursing assessments on which pain interventions are based. Patients in acute pain would benefit from this improved scientific basis for pain assessment.

Neuropathic (NP) pain is a debilitating chronic pain disorder that is a challenge to diagnose and an even greater challenge to treat. Commonly described as burning or shock-like, NP pain is characteristically resistant to traditional analgesic therapy. This thesis project aimed to investigate the potential therapeutic benefit of delta opioid receptor (δOR)-selective agonists in the management of NP pain. In the current experiments, rats that underwent unilateral sciatic nerve injury displayed characteristic behavioural manifestations including cold and thermal hyperalgesia as well as tactile allodynia in the ipsilateral hind paw. The spinal administration of DLT, a δOR-selective agonist, dose-dependently reversed tactile allodynia in NP rats and attenuated cold and thermal hypersensitivities. Moreover, DLT produced greater antinociceptive effects in NP rats compared with controls in the cold water paw withdrawal, hot water tail flick, and thermal plantar box tests. Nerve injury-induced augmentation in δOR function was dependent on nociceptive afferents, since the effect was absent in NP rats that received neonatal treatment with capsaicin. Furthermore, it was not due to increased δOR biosynthesis as western blots and immunohistochemistry revealed no change in spinal δOR protein. We hypothesized that an alternative mechanism, such as redistribution of receptors within the neuron, may underlie δOR function changes. Using immunogold electron microscopy, we showed that nerve injury indeed increased the cell surface expression of δORs within dendritic profiles of the dorsal horn via redistribution of existing receptors. Interestingly, this event was observed bilaterally in the deep dorsal horn, with no effect in the superficial laminae. The mechanisms underlying nerve injury-induced δOR trafficking remain unclear however we may take cues from other δOR trafficking events. We showed that concomitant treatment of rats with morphine and a glial inhibitor prevented both the activation of spinal glia and the changes in δOR agonist effects observed with morphine alone, suggesting that glial activity contributes to morphine-induced δOR trafficking in vivo and may provide insight into the mechanisms underlying nerve injury-induced δOR trafficking. Collectively, these studies reveal an important role of δORs in modulating pain symptoms associated with nerve injury, supporting further exploration of δORs as novel therapeutic targets in the treatment of NP pain. / Thesis (Ph.D, Pharmacology & Toxicology) -- Queen's University, 2009-04-20 14:46:29.83

Neuropathic (NP) pain is a debilitating form of chronic pain that can result from a variety of disease states that target the sensory nervous system. NP pain can manifest as burning or shooting pain, and is commonly refractory to traditional analgesics including opioids. Clinically used opioids target the mu opioid receptors (MORs); preclinical reports, however, suggest that the delta opioid receptor (DOR) may be a valid target. It is now accepted that MORs and DORs oligomerize in heterologous expression systems and exhibit novel pharmacology distinct from their monomers. This research aimed to utilize both functional and molecular evidence to identify if a heteromeric mu-delta opioid receptor oligomer (M/DOR) forms in vivo and whether it is upregulated in NP pain. In an animal model of NP pain, animals displayed characteristic behaviours including protecting of the ipsilateral hindpaw from environmental stimuli, and mechanical allodynia in this paw. Behavioural studies reported that acute injection of DOR- selective agonists that bind M/DOR produced enhanced thermal antinociception and reversed mechanical allodynia in NP rats. DOR agonists that have low binding affinity for M/DOR did not produce enhanced thermal antinociception but did reverse mechanical allodynia in NP rats. Molecular studies were employed to characterize the molecular species of ORs in the lumbar spinal cord. Isolated spinal cord membranes were subjected to coimmunoprecipitation with a M/DOR antibody. Co-immunoprecipitation was unable to conclusively identify changes in M/DOR levels in the dorsal horn but did confirm that such a species exists in vivo. Furthermore, antibody characterization was completed to determine if the commercial antibodies used were labeling the appropriate OR proteins. HEK293T cells transfected with MOR and/or DOR plasmids were used in Western blotting and immunocytochemistry protocols to test commercially available antibodies. These studies determined that MOR and DOR antibodies do label their respective OR type, but also recognize additional proteins (non-specifically) in Western blotting protocols. In conclusion, behavioural studies revealed a putative role for M/DOR agonists in the treatment of NP pain; however, more sensitive tools and protocols must be developed before molecular experiments are able to identify quantifiable changes with endogenous M/DORs. / Thesis (Master, Pharmacology & Toxicology) -- Queen's University, 2009-09-24 12:43:58.472

The endogenous opioid system may be involved in the pathogenesis of arrhythmias and produce deleterious haemodynamic effects in patients with myocardial ischaemia and/or cardiac failure. Plasma concentrations of β-endorphin, a potent opioid peptide, were elevated in 31/42 patients with acute myocardial infarction, 3/18 with unstable angina, 3/34 with chronic heart failure, 8/28 with acute heart failure and 10/14 with cardiogenic shock. (Met)enkephalin levels were generally normal. There was no independent statistical relationship between β-endorphin concentrations after myocardial infarction and the incidence of cardiac arrhythmias. In isolated myocardium, the opioid antagonists naloxone and nalmafene, and morphine, an agonist, all produced Class III antiarrhythmic effects. Naloxone enhanced the reduction in maximum upstroke velocity produced by hyperkalaemia and post-repolarization refractoriness developed. During myocardial ischaemia the Class III effects of naloxone were gradually lost but both racemic naloxone (active at opioid receptors) and d-naloxone (inactive) reduced the rate of rise of extracellular potassium concentration and preserved resting membrane potential. The fall in maximum upstroke velocity during ischaemia was enhanced by both compounds suggesting an additional Class I effect. In human studies, despite employing high doses of naloxone, it was only possible to show a minor prolongation of repolarization. In patients with coronary heart disease, naloxone administered by both intracoronary and intravenous routes had no effect on coronary blood flow. In patients with heart failure naloxone had no significant effects on a range of haemodynamic parameters, exercise performance or levels of dyspnoea and fatigue.