Implementing guidelines for cancer pain management: results of a randomized controlled clinical trial.

PURPOSE: Pain and symptom management is an integral part of the clinical practice of oncology. A number of guidelines have been developed to assist the clinician in optimizing comfort care. We implemented clinical guidelines for cancer pain management in the community setting and evaluated whether these guidelines improved care. PATIENTS AND METHODS: Eighty-one cancer patients, aged 37 to 76 years, were enrolled onto a prospective, longitudinal, randomized controlled study from the outpatient clinic settings of 26 western Washington-area medical oncologists. A multilevel treatment algorithm based on the Agency for Health Care Policy and Research Guidelines for Cancer Pain Management was compared with standard-practice (control) pain and symptom management therapies used by community oncologists. The primary outcome of interest was pain (Brief Pain Inventory); secondary outcomes of interest were all other symptoms (Memorial Symptom Assessment Scale) and quality of life (Functional Assessment of Cancer Therapy Scale). RESULTS: Patients randomized to the pain algorithm group achieved a statistically significant reduction in usual pain intensity, measured as slope scores, when compared with standard community practice (P < .02). Concurrent chemotherapy and patient adherence to treatment were significant mediators of worst pain. There were no significant differences in other symptoms or quality of life between the two treatment groups. CONCLUSION: This guideline implementation study supports the use of algorithmic decision making in the management of cancer pain. These findings suggest that comprehensive pain assessment and evidence-based analgesic decision-making processes do enhance usual pain outcomes.

Structural basis for selective inhibition of Src family kinases by PP1.

BACKGROUND: Small-molecule inhibitors that can target individual kinases are powerful tools for use in signal transduction research. It is difficult to find such compounds because of the enormous number of protein kinases and the highly conserved nature of their catalytic domains. Recently, a novel, potent, Src family selective tyrosine kinase inhibitor was reported (PP1). Here, we study the structural basis for this inhibitor's specificity for Src family kinases. RESULTS: A single residue corresponding to Ile338 (v-Src numbering; Thr338 in c-Src) in Src family tyrosine kinases largely controls PP1's ability to inhibit protein kinases. Mutation of Ile338 to a larger residue such as methionine or phenylalanine in v-Src makes this inhibitor less potent. Conversely, mutation of Ile338 to alanine or glycine increases PP1's potency. PP1 can inhibit Ser/Thr kinases if the residue corresponding to Ile338 in v-Src is mutated to glycine. We have accurately predicted several non-Src family kinases that are moderately (IC(50) approximately 1 microM) inhibited by PP1, including c-Abl and the MAP kinase p38. CONCLUSIONS: Our mutagenesis studies of the ATP-binding site in both tyrosine kinases and Ser/Thr kinases explain why PP1 is a specific inhibitor of Src family tyrosine kinases. Determination of the structural basis of inhibitor specificity will aid in the design of more potent and more selective protein kinase inhibitors. The ability to desensitize a particular kinase to PP1 inhibition of residue 338 or conversely to sensitize a kinase to PP1 inhibition by mutation should provide a useful basis for chemical genetic studies of kinase signal transduction.

Investigating the educational needs of licensed nursing staff and certified nursing assistants in nursing homes regarding end-of-life care.

Nursing homes care for people at the end of life (EOL). There is evidence to suggest, however, that nursing staff in these settings is often unprepared to provide a high level of EOL care. This article reports the findings from three preliminary studies that investigated the needs of licensed staff and certified nursing assistants in nursing homes regarding EOL care. The studies involved needs assessment surveys, focus group interviews with staff members, and telephone interviews with nursing home administrators. Data show that the major needs included a lack of knowledge and skills in symptom management; communication difficulties; conflicts with families and physicians; and emotional distress in dealing with time constraints and attachment to residents. Implications for nursing home staff education are described.

Assessing the educational needs and concerns of nursing home staff regarding end-of-life care.

The purpose of this study was to explore and describe the educational needs and concerns of licensed nursing staff and certified nursing assistants (CNAs) regarding end-of-life (EOL) care. Focus group interviews were conducted at two nursing homes in the Pacific Northwest. Separate interviews were conducted for licensed staff (RNs and LPN/LVNs) and CNAs. A total of 15 licensed staff and 39 CNAs participated in the study. Interviews were transcribed and themes were extracted through consensus reached by three investigators. The major concerns of these nursing home staff focused on symptom management, communication and interactions, goals of care, role delineation, time constraints, self-care needs, and emotional attachment to residents. Although both groups described similar themes, specific issues within each topic often were different for licensed staff and CNAs. These findings can be used to guide the design of educational programs aimed at assisting nursing home staff in providing high level end-of-life care.

Factors hindering patients' use of medications for cancer pain.

OBJECTIVES: The purpose of this study was to explore the reasons that cancer patients with pain find it difficult to adhere to analgesic therapy. MATERIALS AND METHODS: Twenty-one patients with advanced cancer with pain were interviewed using a semistructured schedule of questions. Participants were asked to describe their decision making regarding analgesics and the factors that made it difficult for them to take analgesics prescribed for their pain. They also were asked to describe their relationships with their healthcare providers. Themes were identified and refined using qualitative analytic techniques. Two investigators independently coded all data to ensure that findings accurately reflected participants' experiences. RESULTS: Findings reveal several factors that hindered analgesic use and the specific ways in which patients evaluated these factors in making decisions about taking pain medication. The provider-patient factors that impeded analgesic use also were described. Finally, the common use of nonpharmacologic methods of pain control offers insight into the role of these therapeutic strategies in achieving pain relief and decreasing analgesic use. CONCLUSIONS: The findings underscore the importance of early intervention to address barriers to analgesic use. Some barriers may be overcome through educational efforts. The findings suggest, however, that consistent, repeated patient education often may not be sufficient to subdue patients' negative thoughts about taking the medication. Other approaches, such as changing medications or assisting the patient to use nonpharmacologic pain strategies, may prove more successful.

Phage-display evolution of tyrosine kinases with altered nucleotide specificity.

The problem of identifying downstream targets of kinase phosphorylation remains a challenge despite technological advances in genomics and proteomics. A recent approach involves the generation of kinase mutants that can uniquely use "orthogonal" ATP analogs to phosphorylate substrates in vivo. Using structure-based design, mutants of several protein kinase superfamily members have been found; robust and general methods are needed, however, for altering the nucleotide specificity of the remaining kinases in the genome. Here we demonstrate the application of a new phage display technique for direct functional selection to the identification of a tyrosine kinase mutant with the ability to use N6-benzyl-ATP. Our method produces, in five rounds of selection, a mutant identical to the best orthogonal Src kinase found to date. In addition, we isolate from a larger library of kinase mutants a promiscuous clone capable of using many different ATP analogs. This approach to engineering orthogonal kinases, combined with others, will facilitate the mapping of phosphorylation targets of any kinase in the genome.

Unnatural ligands for engineered proteins: new tools for chemical genetics.

Small molecules that modulate the activity of biological signaling molecules can be powerful probes of signal transduction pathways. Highly specific molecules with high affinity are difficult to identify because of the conserved nature of many protein active sites. A newly developed approach to discovery of such small molecules that relies on protein engineering and chemical synthesis has yielded powerful tools for the study of a wide variety of proteins involved in signal transduction (G-proteins, protein kinases, 7-transmembrane receptors, nuclear hormone receptors, and others). Such chemical genetic tools combine the advantages of traditional genetics and the unparalleled temporal control over protein function afforded by small molecule inhibitors/activators that act at diffusion controlled rates with targets.

An educational implementation of a cancer pain algorithm for ambulatory care.

Algorithms are proposed as a means of operationalizing guidelines or standards for cancer pain management. Professional education is used as the means to translate knowledge into practice. Outcomes measurement is the gold standard for validating improvement. This study used an educational intervention to transfer knowledge on implementing a previously tested algorithm for cancer pain management into community outpatient oncology clinics and, subsequently, measuring patient outcomes. Physicians and nurses from 9 Puget Sound clinics were randomized by institution blocks to either "training" or "no training." Role model physician/nurse teams were the core faculty for a day-long seminar. Written reference materials and documentation tools were provided to the trained physician/nurse teams. A total of 105 patients of trained and untrained providers were accrued and assessed over 4 months. Patients of trained providers had a significant reduction in usual pain over the 4 months of data collection compared with patients of untrained providers (t = 2.0; p = .05). Improvements were modest in the prescription of opioid analgesics and dramatic in the prescription of co-analgesics for neuropathic pain. There was a clear deterioration in the impact of the training over time. The most significant effect occurred within the first 140 days after the intervention and was followed by a gradual return to baseline practice. In conclusion, algorithmic interventions can be successfully transferred into community practice, but further work must be performed to develop methods for securing retention of knowledge and maintaining improved outcomes.