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Controlled Release Analgesics

One of the most important medical necessities on the battlefield is pain relief after combat injury.  This is a crucial requirement because acute trauma causes very painful tissue and bone disruption and not infrequently, individuals who have been wounded cannot be immediately removed from the battlefield.  This can necessitate that analgesia be maintained for prolonged periods before an individual can be moved to an acute care facility where the injuries can be better addressed. These individuals can create logistic and moral issues for fellow soldiers who need to continue combat.  In addition, chronic battlefield pain that is inadequately relieved is a major determinant of post traumatic stress disorders.  These problems therefore make adequate battlefield pain relief essential. 

The unique conditions of battlefield trauma require a complex pain relief solution.  First, there needs to be some form of controlled release therapeutic that could relieve pain over a prolonged period.  This therapeutic needs to be easily administered such as by intramuscular auto-injector and should not require monitoring in an ongoing combat situation.  Unfortunately, the most effective pain medications, narcotic analgesics, are short acting and the doses of drug that cause analgesia are not greatly separated from those that cause serious side effects such as respiratory depression and hypotension. To provide autonomously effective narcotic analgesia over longer periods of time in the battlefield, a controlled release narcotic for sustained analgesia in the absence of respiratory depression is required. 

Hemoglobin Protein

Figure 1: Hemoglobin Protein
Each green HEME structure can bind 1 oxygen molecule. O2 sat is 50% when 2 of the 4 HEMEs are occupied with oxygen

Oxyhemoglobin Dissociation Curve

Figure 2: Oxyhemoglobin Dissociation Curve
Derived from: www.ventworld.com/resources/oxydisso/oxydisso.html

To address the unique requirements for analgesia under battlefield conditions, we are developing a poly-amidoamine (PAMAM) dendrimer-based multifunctional nanodevice to engineer a controlled release analgesic that will be safe to administer under battlefield conditions without close monitoring of the injured.  This will consist of a controlled release system of Morphine / Naloxone with a built in feedback system that controls the release of Naloxone, based upon the injured soldier's condition. Naloxone is used to counter certain effects of Morphine such as respiratory depression.  We plan to develop a combination drug that can be delivered to the injured soldier on the battlefield, possibly by self-administration with an intramuscular auto-injector or by fellow war fighters or medics.  

The Research Team
In order to address the unique requirements for analgesia, we assembled a core, multidisciplinary team of a former military physician, an anesthesiologist, a (trauma) surgeon, medicinal chemists, polymer chemists, organic chemists, analytical chemists, a physicist, and biologists.
 

Publications

Huang B, Tang S, Desai A, Cheng X, Kotlyar A, Van Der Spek A, Thomas TP, Baker JR Jr.  Human plasma-mediated hypoxic activation of indolequinone-based naloxone pro-drugs.  Bioorganic & Medicinal Chemistry Letters, Volume 19, Issue 17, 1 September 2009, pgs. 5016-5020.


This project is funded by Defense Advanced Research Projects Agency, Department of Defense.

 

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