Process to develop a State Model Law to reduce prescription drug trafficking while protecting pain management

This paper will discuss the intersection of pill mills and the under-treatment of pain, while addressing the unintended consequence that cracking down on pill mills actually has on medical professionals' treatment of legitimate pain in clinical settings. Moreover, the impact each issue has on the spectrum of related policy, regulatory issues and legislation will be analyzed while addressing the national impact on medical care. Lastly, this paper will outline a process to develop a State Model Law on this subject. This process will include suggestions for the future and how we can move forward to adequately address public safety needs and how we can attempt to mitigate the unintended impact prescription drug trafficking has had on a patient's right to appropriate pain management. This balance is achievable and this paper will address ways we can find this elusive balancing point through the development of a State Model Law. ^

Studies on behavioral regulations of morphine tolerance in rats

Opioids remain the drugs of choice in chronic pain treatment, but opioid tolerance, defined as a decrease in analgesic effect after prolonged or repeated use, dramatically limits their clinical utility. Opioid tolerance has classically been studied by implanting spinal catheters in animals for drug administration. This procedure has significant morbidity and mortality, as well as causing an inflammatory response which decreases the potency of opioid analgesia and possibly affects tolerance development. Therefore, we developed and validated a new method, intermittent lumbar puncture (Dautzenberg et al.), for the study of opioid analgesia and tolerance. Using this method, opioid tolerance was reliably induced without detectable morbidity. The dose of morphine needed to induce analgesia and tolerance using this method was about 100-fold lower than that required when using an intrathecal catheter. Only slight inflammation was found at the injection site, dissipated within seven mm. ^ DAMGO, an opioid μ receptor agonist, has been reported to inhibit morphine tolerance, but results from different studies are inconclusive. We evaluated the effect of DAMGO on morphine tolerance using our newly-developed ILP method, as well as other intrathecal catheter paradigms. We found that co-administration of sub-analgesic DAMGO with morphine using ILP did not inhibit morphine tolerance, but instead blocked the analgesic effects of morphine. Tolerance to morphine still developed. Tolerance to morphine can only be blocked by sub-analgesic dose of DAMGO when administered in a lumbar catheter, but not in cervical catheter settings. ^ Finally, we evaluated the effects of Gabapentin (GBP) on analgesia and morphine tolerance. We demonstrated that GBP enhanced analgesia mediated by both subanalgesic and analgesic doses of morphine although GBP itself was not analgesic. GBP increased potency and efficacy of morphine. GBP inhibited the expression, but not the development, of morphine tolerance. GBP blocked tolerance to analgesic morphine but not to subanalgesic morphine. GBP reversed the expression of morphine tolerance even after tolerance was established. These studies may begin to provide new insights into mechanisms of morphine tolerance development and improve clinical chronic pain management. ^

Why does low dose morphine augment fentanyl analgesia?

Opioids dominate the field of pain management because of their ability to provide analgesia in many medical circumstances. However, side effects including respiratory depression, constipation, tolerance, physical dependence, and the risk of addiction limit their clinical utility. Fear of these side effects results in the under-treatment of acute pain. For many years, research has focused on ways to improve the therapeutic index (the ratio of desirable analgesic effects to undesirable side effects) of opioids. One strategy, combining opioid agonists that bind to different opioid receptor types, may prove successful.^ We discovered that subcutaneous co-administration of a moderately analgesic dose of the mu-opioid receptor (MOR) selective agonist fentanyl (20μg/kg) with subanalgesic doses of the less MOR-specific agonist morphine (100ng/kg-100μg/kg), augmented acute fentanyl analgesia in rats. Parallel [35S]GTPγS binding studies using naïve rat substantia gelatinosa membrane treated with fentanyl (4μM) and morphine (1nM-1pM) demonstrated a 2-fold increase in total G-protein activation. This correlation between morphine-induced augmentation of fentanyl analgesia and G-protein activation led to our proposal that interactions between MORs and DORs underlie opioid-induced augmentation. We discovered that morphine-induced augmentation of fentanyl analgesia and G-protein activity was mediated by DORs. Adding the DOR-selective antagonist naltrindole (200ng/kg, 40nM) at doses that did not alter the analgesic or G-protein activation of fentanyl, blocked increases in analgesia and G-protein activation induced by fentanyl/morphine combinations. Equivalent doses of the MOR-selective antagonist cyprodime (20ng/kg, 4nM) did not block augmentation. Substitution of the DOR-selective agonist SNC80 for morphine yielded similar results, further supporting our conclusion that interactions between MORs and DORs are responsible for morphine-induced augmentation of fentanyl analgesia and G-protein activation. Confocal microscopy of rat substantia gelatinosa showed that changes in the rate of opioid receptor internalization did not account for these effects.^ In conclusion, fentanyl analgesia augmentation by subanalgesic morphine is mediated by increased G-protein activation resulting from functional interactions between MORs and DORs, not changes in MOR internalization. Additional animal and clinical studies are needed to determine whether side effect incidence changes following opioid co-administration. If side effect incidence decreases or remains unchanged, these findings could have important implications for clinical pain treatment. ^

Advanced Protein Modeling Method: Benchmarking and Applications in Computer-Aided Drug Discovery

Development of homology modeling methods will remain an area of active research. These methods aim to develop and model increasingly accurate three-dimensional structures of yet uncrystallized therapeutically relevant proteins e.g. Class A G-Protein Coupled Receptors. Incorporating protein flexibility is one way to achieve this goal. Here, I will discuss the enhancement and validation of the ligand-steered modeling, originally developed by Dr. Claudio Cavasotto, via cross modeling of the newly crystallized GPCR structures. This method uses known ligands and known experimental information to optimize relevant protein binding sites by incorporating protein flexibility. The ligand-steered models were able to model, reasonably reproduce binding sites and the co-crystallized native ligand poses of the β2 adrenergic and Adenosine 2A receptors using a single template structure. They also performed better than the choice of template, and crude models in a small scale high-throughput docking experiments and compound selectivity studies. Next, the application of this method to develop high-quality homology models of Cannabinoid Receptor 2, an emerging non-psychotic pain management target, is discussed. These models were validated by their ability to rationalize structure activity relationship data of two, inverse agonist and agonist, series of compounds. The method was also applied to improve the virtual screening performance of the β2 adrenergic crystal structure by optimizing the binding site using β2 specific compounds. These results show the feasibility of optimizing only the pharmacologically relevant protein binding sites and applicability to structure-based drug design projects.

Long-term survival after multidisciplinary management of resected pancreatic adenocarcinoma.

INTRODUCTION: Actual 5-year survival rates of 10-18% have been reported for patients with resected pancreatic adenocarcinoma (PC), but the use of multimodality therapy was uncommon in these series. We evaluated long-term survival and patterns of recurrence in patients treated for PC with contemporary staging and multimodality therapy. METHODS: We analyzed 329 consecutive patients with PC evaluated between 1990 and 2002 who underwent resection. Each received a multidisciplinary evaluation and a standard operative approach. Pre- or postoperative chemotherapy and/or chemoradiation were routine. Surgical specimens of 5-year survivors were re-reviewed. A multivariate model of factors associated with long-term survival was constructed. RESULTS: Patients underwent pancreaticoduodenectomy (n = 302; 92%), distal (n = 20; 6%), or total pancreatectomy (n = 7; 2%). A total of 108 patients (33%) underwent vascular reconstruction, 301 patients (91%) received neoadjuvant or adjuvant therapy, 157 specimens (48%) were node positive, and margins were microscopically positive in 52 patients (16%). Median overall survival and disease-specific survival was 23.9 and 26.5 months. Eighty-eight patients (27%) survived a minimum of 5 years and had a median overall survival of 11 years. Of these, 21 (24%) experienced recurrence, 7 (8%) after 5 years. Late recurrences occurred most frequently in the lungs, the latest at 6.7 years. Multivariate analysis identified disease-negative lymph nodes (P = .02) and no prior attempt at resection (P = 0.01) as associated with 5-year survival. CONCLUSIONS: Our 27% actual 5-year survival rate for patients with resected PC is superior to that previously reported, and it is influenced by our emphasis on detailed staging and patient selection, a standardized operative approach, and routine use of multimodality therapy.

Effectiveness of an early postoperative feeding protocol

Background. The increasing emphasis on medical outcomes and cost containment has made it imperative to identify patient populations in which aggressive nutritional care can improve quality of care. The aim of this prospective study was to implement a standardized early jejunal feeding protocol for patients undergoing small and large bowel resection, and to evaluate its effect on patient outcome and cost.^ Methods. Treatment patients (n = 81) who met protocol inclusion criteria had a jejunal feeding tube inserted at the time of surgery. Feeding was initiated at 10 cc/hour within 12 hours after bowel resection and progressed if hemodynamically stable. The control group (n = 159) received usual care. Outcome measures included postoperative length of stay, total direct cost, nosocomial infection rate and health status (SF-36) scores.^ Results. By postoperative day 4, the use of total parenteral nutrition (TPN) was significantly greater in the control group compared to the treatment group; however, total nutritional intake was significantly less. Multiple regression analysis indicated an increased likelihood of infection with the use of TPN. A reduction of 3.5 postoperative days (p =.013) with 4.3 fewer TPN days per patient (p =.001) and a 9.6% reduction in infection rate (p =.042) was demonstrated in the treatment group. There was no difference in health status scores between groups at discharge and 3 months post-discharge.^ Conclusion. These positive outcomes and an average total cost savings of $4,145 per treatment patient indicate that the treatment protocol was effective. ^

Blood-oxygen-level-dependent (BOLD) signal changes in total cortex and subcortex, pain, reward, and vigilance regions during mechanical pressure pain after morphine administration

Morphine is the most common clinical choice in the management of severe pain. Although the molecular mechanisms of morphine have already been characterized, the cerebral circuits by which it attenuates the sensation of pain have not yet been studied in humans. The objective of this two-arm (morphine versus placebo), between-subjects study was to examine whether morphine affects pain via pain-related cortical circuits, but also via reward regions that relate to the motivational state, as well as prefrontal regions that relate to vigilance as a result of morphine's sedative effects. Cortical activity was measured by the blood-oxygen-level-dependent (BOLD) signal changes using functional magnetic resonance imaging (fMRI). ^ The novelty of this study is at three levels: (i) to develop a methodology that will assess the average BOLD signal across subjects for the pain, reward, and vigilance cortical systems; (ii) to examine whether the reward and/or sedative effects of morphine are contributing factors to cortical regions associated with the motivational state and vigilance; and (iii) to propose a neuroanatomical model related to the opioid-sensitive effects of reward and sedation as a function of cortical activity related to pain in an effort to assess future analgesics. ^ Consistent with our hypotheses, our findings showed that the decrease in total pain-related volume activated between the post- and the pre-treatment morphine group was about 78%, while the post-treatment placebo group displayed only a 5% decrease when compared to pre-treatment levels of activation. The volume increase in reward regions was 451% in the post-treatment compared to the pre-treatment morphine condition. Finally, the volumetric decrease in vigilance regions was 63% in the posttreatment compared to the pre-treatment morphine condition. ^ These findings imply that changes in the blood flow of the reward and vigilance regions may be contributing factors in producing the analgesic effect under morphine administration. Future studies need to replicate this study in a higher resolution fMRI environment and to assess the proposed neuroanatomical model in patient populations. The necessity of pain research is apparent, since pain cuts across different diseases especially chronic ones, and thus, is recognized as a vital public health developing area. ^