A randomized double blind, placebo controlled study of vitamin D to ameliorate sickle cell chronic pain

s The Journal of Pain S73 (388) A randomized double blind, placebo controlled study of vitamin D to ameliorate sickle cell chronic pain I Osunkwo, T Ziegler, J Alvarez, J George, K Cherry, J Rhodes, O Adisa, S OforiAcquah, C McCracken, S Ghosh, J Eckman, V Tangpricha, and C Dampier; Emory University, Children’s Healthcare of Atlanta, Atlanta, GA Pain is the hallmark symptom of sickle cell disease (SCD) and accounts for majority of morbidity and healthcare utilization associated with the disease. Low vitamin D status leads to osteoporosis, increased fracture risk and chronic back/ extremity pain in adults however there is limited data on its clinical relevance in SCD. Our objective was to determine the efficacy and safety of vitamin D in improving pain in SCD. Any sickle genotype between 7 and 21 years was eligible. We excluded sickle nephropathy, serum Cr>1.5, Ca 11mg/dL, ALT>3ULN, malabsorption, oral steroids, thiazides, depot-provera, phenobarbital, phosphenytoin, previous treatment with vitamin D. Subjects (n=39) were randomized to receive high dose vitamin D (240,000-600,000IU) or placebo over 6 weeks. Pain-days were monitored using daily diary. Serum 25-hydroxyvitamin D (25OHD) was measured and Peds QoL v4 administered at weeks 8, 16, 24. Statistical analyses used SAS 9.2 (Cary, NC). Serum 25OHD increased briskly (21.3 to 52.2ng/ml byweek 8) in treatment arm, drifting down to 31.5ng/mLbyweek 24 compared to placebo. Serum 25OHDwas negatively associatedwith number of pain days (r = -0.680; p=0.019) indicating that higher serum 25OHD were associated with fewer pain days. Vitamin D levels were also positively associated with physical QoL score (rs = 0.22; p=0.036), indicating that higher 25OHD levels were associated with higher physical QoL measures. As expected, the number of pain days was negatively associated with physical QoL scores (rs = -0.25; p=0.022). There was a significant three way interaction between the number of pain days between visits, randomization group and visit number (p=0.391) such that the higher the 25OHD level the fewer pain days between visits. This suggests a benefit of vitamin D in improving pain and quality of life in SCD. Larger prospective studies with longer duration are needed to confirm these effects. (389) Design of long-acting local anesthetics patterned on the guanidinium toxins J Mulcahy, M Klukinov, C Shea, D Behera, G Miljanich, S Biswal, J Du Bois, and D Yeomans; Stanford University, Stanford, CA Existing treatment options for moderate to severe pain, including opioids, are not always effective and suffer from awide range of side effects, including potential for addiction and abuse. The guanidinium toxins (GTxs) are a class of potent, naturally occurring small molecules that inhibit voltage-gated sodium ion channels (NaV) by binding to the channel pore and blocking Na + ion transit. GTxs are believed to inhibit six of the nine mammalian isoforms of the voltage-gated Na channel at single-digit nanomolar concentrations. Significantly, the cardiac isoform, NaV1.5, is resistant; greatly reducing the risk of cardiac toxicity as compared with existing, clinically employed NaV inhibitors (lidocaine, bupivacaine, etc.). GTxs have been successfully evaluated in human clinical trials for a number of indications including pain, chronic headache and anal fissures. Here, we demonstrate that modification of the GTxs through de novo chemical synthesis has made possible the construction of analogues of these compounds having improved pharmacologic properties. Novel GTxs have been synthesized and tested as local anesthetics and/or analgesics in certain rat behavioral assays. Derivatives have been identified that provide anesthesia lasting between one and nine days. In addition, the synthetic pathway allows for strategies for the creation of NaV-subtype selective blockers. No significant toxicity has been observed to date at doses as high as 15 times the minimum effective dose. We continue to evaluate the ADMET properties of our GTx lead compounds through animal behavioral and radiological studies, and expect that such information will help guide the development of a long-lasting GTx-based therapeutic that offers significant improvements over current treatment options for moderate to severe pain. (390) Abuse-resistant opioid prodrugs that demonstrate oral overdose protection T Jenkins, C Husfeld, J Cremin, A Kolesnikov, L Pelc, J Seroogy, and J Wray; Pharmacofore Inc., San Carlos, CA In an effort to address the widespread abuse of prescription opioids, we have created a novel molecular-scale delivery technology. We have developed an abuse-resistant hydromorphone prodrug (PF329) for the treatment of moderate-to-severe pain. PF329 was designed to release hydromorphone only when exposed to specific physiologic conditions (i.e., exposure to the digestive enzyme trypsin in the small intestine following oral ingestion). Preclinical data supporting the key non-oral and oral abuse deterrent features of PF329 will be presented. These include 1) a demonstration of robust tamper-resistance when exposed to a variety of common household chemicals and enzymes in vitro, 2) inactivity at the mu-opioid receptor (PF329 EC50 value = 6.3 mM vs hydromorphone EC50 value = 2.6 nM) and 3) minimal systemic conversion ( 0.1%) of PF329 to hydromorphone following intravenous administration (rat). The unique ‘‘bio-conditional’’ delivery mechanism of PF329 produces an extended release pharmacokinetic profile of hydromorphone that cannot be altered by chewing, crushing, or the co-ingestion of alcohol. Pharmacokinetic data regarding dose proportionality and effect of food on the hydromorphone delivered by PF329 will also be presented. Data from in vivo enzyme inhibition studies aimed at elucidating the specific role of trypsin in the bio-activation of PF329 provided a potential mechanism for achieving oral overdose protection. The bioavailability of hydromophone delivered from increasing amounts of PF329 can be controlled via the co-formulation of a fixed ratio of a small-molecule trypsin inhibitor. This process is shows the potential to i) produce a targeted hydromorphone plasma concentration-time profile when a single dose of PF329 and trypsin inhibitor is ingested, and ii) provide multi-pill abuse resistance and overdose protection by progressively decreasing the bioavailability of hydromorphone when multiple doses are co-ingested. This poster in intended to be complementary to our phase I clinical trial data for PF329. (391) Bridging from conventional marketed extended release formulations to new tamper resistant alternatives H Stahlberg, M Brett, E Galia, J Ossig, and B Wenge; Clinical Research Services,