Anthony L. Vaccarino - US grants

DESCRIPTION: Applicant's Abstract The present proposal is aimed at using basic animal research to understand the relative contribution of behavioral and biological factors to analgesic tolerance in the clinical setting. We propose to characterize the mechanisms that underlie the development of tolerance to morphine analgesia by testing the hypothesis that "stress-triggered" changes during pain influence the therapeutic actions of morphine. More specifically, we propose that the effects of pain on the development of tolerance to morphine analgesia depends on corticosterone activity during pain. We will test this hypothesis in a rat model that approximates the clinical use of opiates for pain control, in which we recently showed that repeated injections of morphine do not produce analgesic tolerance when administered in the presence of pain, but do in the absence of pain. To determine the role of corticosterone in the development of tolerance to morphine analgesia during pain we will establish a relationship between the pain, tolerance and corticosterone activity. Our hypothesis predicts that pharmacological blockade of pain-triggered corticosterone activity will prevent the blockade of tolerance by pain. In addition, we will establish a relationship between strain differences in pain-triggered corticosterone activity and the development of tolerance to morphine analgesia during pain. Our hypothesis predicts that a strain of rat identified to lack typical stress-induced endocrine responses (Lewis strain) will not show an increase in corticosterone following pain, and thus will not show a blockade of tolerance by pain. This proposal will also evaluate the biobehavioral factors that influence the development of tolerance during pain by examining the contribution of type of pain, corticosterone, and method of morphine administration. We will examine the conditions in which pain attenuates tolerance versus conditions in which pain fails to attenuate tolerance. Our hypothesis predicts that the effects of pain and corticosterone on tolerance development can be predicted based on the presence or absence of environmental cues associated with morphine administration. The identification of the biological and behavioral factors that influence tolerance to morphine analgesia during pain will provide insights into the mechanisms that determine the development of aped tolerance in the clinical setting.

DESCRIPTION (provided by applicant): Combination analgesics, including acetaminophen with opioids, are used extensively for pain management in the elderly (and others). This is, in part, because these combinations can produce analgesia that is additive or synergistic, and the adverse effects produced by the combinations can be less than those produced by equianalgesic doses of either component alone. Even so, the acetaminophen in these combinations can cause hepatotoxicity after ingestion of large doses or from chronic use, particularly in the elderly or when liver function is compromised. The opioid dosages need to be escalated in response to the tolerance that is developed from chronic use, increasing the occurrence of adverse side effects in the elderly. We have been exploring a series of new and proprietary derivatives of acetaminophen, in which the lead compound (SCP-1) has good oral efficacy in both young and aged animals, and produces little, if any, hepatotoxicity. This Phase I SBIR project explores the feasibility that combinations of SCP-1 + codeine can have synergistic effects comparable to or better than acetaminophen + codeine combinations, but with reduced side effects, in models of acute and chronic pain management using young and old animals. It will also determine (in both young and old animals) the development of tolerance and dependence after chronic dosing, as well as hepatotoxicity after chronic and acute dosing. If the SCP-1 with codeine is shown to be more efficacious and/or less toxic than acetaminophen with codeine, further drug development will be proposed under a Phase II SBIR with eventual clinical trials in elderly patients who require management of acute or chronic pain.

DESCRIPTION (provided by applicant): Acetaminophen is used extensively in the management of mild to moderate pain. Even so, acetaminophen can cause hepatotoxicty after ingestion of large doses or from chronic use of smaller doses, particularly in the elderly, when liver function is compromised, or with concurrent alcohol use. Acetaminophen-induced liver injury is due not to the drug itself but to the formation of a toxic metabolite that normally would be detoxified by conjugation with glutathione. However, with an acute overdose or chronic use, glutathione stores are depleted and the toxic metabolite binds to liver cell proteins and causes hepatic necrosis. We have been exploring a series of new and proprietary acetaminophen derivatives, in which the lead compound (SCP-1) has good oral efficacy and produces little if any hepatotoxicity. Because the metabolic conversion of SCP-1 to acetaminophen is minimal, SCP-1 has its effects through different pathways than acetaminophen and SCP-1 is not a 'pro-drug' of acetaminophen. This Phase I application explores whether two major SCP-1 metabolites possess analgesic activity without hepatotoxicity in order to (1) understand the mechanisms of SCP-1 drug action, and (2) determine the feasibility of developing these metabolites for use in targeted populations in which the biotransformation of analgesic medications, including acetaminophen or SCP-1, could reduce therapeutic activity and/or increase the unwanted side-effects. It will determine whether the two SCP-1 metabolites have analgesic effects comparable to or better than SCP-1 or acetaminophen in two animal models of pain. It will also determine hepatotoxicity after chronic and acute dosing. If the SCP-1 metabolites show analgesic properties without hepatotoxicity, further drug development will be proposed under a Phase II SBIR with eventual clinical trials in special populations that have high levels of factors that influence the biotransformation of drugs into active metabolites, including patients with liver disease, malnutrition, obesity, genetically determined polymorphisms, concurrent use of drugs that inhibit metabolic enzymes, alcohol use, and the elderly.

DESCRIPTION (provided by applicant): Pain is the most prevalent symptom in cancer patients, and bone metastasis is one of the most common sources of cancer-related pain. In the 3-step guidelines established by the World Health Organization (WHO) non-opioid analgesics (acetaminophen and NSAIDs) are the first step against cancer pain. In step 2, when pain relief is not achieved with non-opioid medications, synergistic opioid/non-opioid combinations (e.g., codeine + acetaminophen) are used. Thus, acetaminophen is a heavily used efficacious treatment for bone cancer-related pain. However, it has been recognized that even at therapeutic doses acetaminophen causes liver toxicity. Cancer patients are exposed to a multitude of chemotherapeutics that tax liver function to the limit, and thus are particularly susceptible to acetaminophen-induced liver toxicity. Therefore, an acetaminophen-like analgesic that does not deplete glutathione stores would increase the ability to treat cancer-related pain with Step 1 and Step 2 medications, and fill an important void in the options available to cancer patients. We are currently exploring a series of new and proprietary derivatives of acetaminophen, in which the lead compound (SCP-1) has good oral efficacy that is synergistic with opioids, and appears to overcome the hepatotoxic shortcomings of acetaminophen. Under this Phase I SBIR project, we will determine the feasibility of using this unique compound as stage 1 and stage 2 treatments of bone cancer pain.

[unreadable] DESCRIPTION (provided by applicant): The therapeutic use of some analgesic compounds is often limited because of potentially adverse and dangerous side effects. However, combinations of analgesics with different mechanisms of action could enhance analgesic efficacy (synergy) while reducing the dose-dependent adverse effects of the individual components. The development of combination analgesics that are synergistic, therefore, would effectively reduce the dose of each compound, thus reducing the adverse effects while maintaining analgesic potency. [unreadable] Combinations of acetaminophen with opioids (i.e., hydrocodone, codeine) are frequently prescribed for acute and chronic pain management. However, although acetaminophen combinations have greater efficacy for moderate to severe pain and are some of the most popular prescription analgesics on the market, it has been recognized that even at therapeutic doses acetaminophen (and combinations containing acetaminophen) can cause liver toxicity. Thus, a drug with a similar analgesic profile to acetaminophen, but with little or no hepatotoxicity, would be a valuable substitute for acetaminophen in these combinations. Phase I supported the development of a non-toxic acetaminophen analog (SCP-1) in which we explored the feasibility of using this compound in combination with other opioid and nonopioid analgesics. Our goal was to identify two SCP-1 combinations (one opioid and one nonopioid) that displayed synergistic analgesic properties, and would be the basis for further drug development in Phase II. Based on their superior synergistic analgesic profile, SCP-1+codeine and SCP-1+clonidine combinations were identified as candidates for further development. Under Phase II support we will evaluate and screen further the analgesic profiles and adverse side-effects of different SCP-1 : codeine and SCP-1 : clonidine combination ratios (i.e. formulations). These results will be the basis for conducting key early stage pre-clinical GLP safety studies under Phase II that will be used in our IND applications to the FDA. In Phase III we will conduct Phase I human clinical trials to evaluate tolerability and oral bioavailability in normal human volunteers, and Phase II human clinical trials to evaluate the combinations in postoperative pain patients. [unreadable] [unreadable]