Background Escalating rates of prescription opioid use and abuse have occurred in the context of efforts to improve the treatment of non-malignant pain. Objectives To characterize the diagnosis and management of non-malignant pain in ambulatory, office-based settings in the United States between 2000 and 2010. Design, setting, and participants Serial cross-sectional and multivariate regression analyses of the National Ambulatory Medical Care Survey (NAMCS), a nationally representative audit of office-based physician visits. Measures (1) Annual visits volume among adults with primary pain symptom or diagnosis; (2) receipt of any pain treatment; and (3) receipt of prescription opioid or non-opioid pharmacologic therapy in visits for new musculoskeletal pain. Results Primary symptoms or diagnoses of pain consistently represented one-fifth of visits, varying little from 2000 through 2010. Among all pain visits, opioid prescribing nearly doubled from 11.3% to 19.6%, whereas non-opioid analgesic prescribing remained unchanged (26%–29% of visits). One-half of new musculoskeletal pain visits resulted in pharmacologic treatment, though the prescribing of non-opioid pharmacotherapies decreased from 38% of visits (2000) to 29% of visits (2010). After adjusting for potentially confounding covariates, few patient, physician or practice characteristics were associated with a prescription opioid rather than a non-opioid analgesic for new musculoskeletal pain, and increases in opioid prescribing generally occurred non-selectively over time. Conclusions Increased opioid prescribing has not been accompanied by similar increases in non-opioid analgesics or the proportion of ambulatory pain patients receiving pharmacologic treatment. Clinical alternatives to prescription opioids may be underutilized as a means of treating ambulatory non-malignant pain.

We describe the rational design and synthesis of B- and A, B-ring-modified camptothecins. The key alpha-hydroxy-delta-lactone pharmacophore in 7-tert-butyldimethylsilyl-10-hydroxycamptothecin (DB-67, 14) displays superior stability in human blood when compared with clinically relevant camptothecin analogues. In human blood 14 displayed a t(1/2) of 130 min and a percent lactone at equilibrium value of 30%. The tert-butyldimethylsilyl group renders the new agent 25-times more lipophilic than camptothecin, and 14 is readily incorporated, as its active lactone form, into cellular and liposomal bilayers. In addition, the dual 7-alkylsilyl and 10-hydroxy substitution in 14 enhances drug stability in the presence of human serum albumin. Thus, the net lipophilicity and the altered human serum albumin interactions together function to promote the enhanced blood stability. In vitro cytotoxicity assays using multiple different cell lines derived from eight distinct tumor types indicate that 14 is of comparable potency to camptothecin and 10-hydroxycamptothecin, as well as the FDA-approved camptothecin analogues topotecan and CPT-11. In addition, cell-free cleavage assays reveal that 14 is highly active and forms more stable top1 cleavage complexes than camptothecin or SN-38. The impressive blood stability and cytotoxicity profiles for 14 strongly suggest that it is an excellent candidate for additional in vivo pharmacological and efficacy studies.

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