Invention:
This invention provides compositions and method of pain treatment using a mu/delta opioid receptor heterodimer (MDOR) antagonist which has improved druggability by nanoformulation and/or glycosylation to increase their bioavailability and efficacy. These modified antagonists and formulations provide for enhancement of opioid agonist therapy's antinociceptive effects, reduction of side effects or adverse effects of opioid agonist therapy, and reduced withdrawal symptoms. Proof-of-concept testing in animals has shown a significant increase in oxymorphone antinociception.
Background:
Opioids continue to be widely used for pain treatment. However, constant opioid treatment is accompanied with serious undesirable effects including drowsiness and mental clouding, nausea and emesis, constipation and in many cases dependence and addiction. Continuous use of opioid therapy also develops analgesic tolerance and hyperalgesia in many patients. These unwanted effects significantly diminish the patients’ quality of life. The mechanisms for these side effects are still largely unclear. However, one particular side effect, namely addiction, is a cause for great concern in pain treatment using opioids.
Prescription opioids can be highly addictive and are widely misused. It has been estimated that the total economic cost of opioid misuse in the United States is $78.5 billion per year. The opioid crisis has been exacerbated by over-prescription of opioid pain-relievers for the treatment of pain. Due at least in part to over-prescription and additive nature of opioids, some who experience chronic pain may suffer undertreatment. In fact, in many parts of the developing world, access to opioids even for acute pain and/or cancer pain can be restricted due to concerns over addiction and overdose. Even in the United States, some patients can suffer from an undertreatment of pain. For example, patients with cognitive impairment and the elderly can be especially susceptible to the central nervous system effects of traditional opioids such as morphine and in some cases are not prescribed enough to meet their pain management needs.
Receptors do not only signal as single units, but can bind to each other to form dimers and oligomers that signal differently from single receptors. In earlier work, the inventors developed a selective antagonist compound for the mu/delta opioid receptor heterodimer (MDOR), and used this ligand to show that the MDOR acted as an opioid negative feedback loop, suppressing pain relief and enhancing side effects. Reversing this effect by treatment with this approach thus has promise in improving opioid pain relief and reducing side effects like withdrawal. However, the compound studied previously is a flexible peptide with poor metabolic stability and blood-brain barrier penetration. The inventors thus sought to improve druggability by developing analogues and formulation.
Applications:
- Pain treatment
- Opioid withdrawal
Advantages:
- Improve pain management
- Avoid withdrawal symptoms
