Opioid Abuse Disorder Treatment Research Study

Background

The NASA Ames Research Center campus houses an animal research facility on its grounds in which various studies are carried out by a number of pharmaceutical/biotech companies. I was fortunate enough to be a part of one of these teams working to address the issue of addiction in opioid use disorder patients. In my laboratory, a small team worked to test the effects of novel compounds and determine which ones possessed the right mix of pharmacological effects to provide patients with a drug that would ease their transition through an otherwise painful withdrawal while helping them to physiologically kick the habit of drug addiction. Our goal was to produce the best drug we could that excelled in the two halves of drug interaction required to kick the patient of their addiction symptoms.

Why it’s important to get it exactly right

The two rescue compounds currently available are Narcan (naloxone),which effectively knocks the opioid receptors loose of opioids, and buprenorphine, which partially removes the opioid from the receptor while providing patients with a slight analgesic. Unfortunately, Narcan works so well to get rid of opioids that patients taking it suffer extremely painful bouts of withdrawal before recovering, and the typical first thing patients do is to seek more drugs which can end up with overdosing. Likewise, patients taking buprenorphine may end up developing a dependency on its mild analgesic and never fully recover either.

In order to develop an ideal opioid use disorder medication, a drug needs to provide enough analgesic to numb the pains of withdrawal while remaining mild enough not to induce a new addiction. That’s where our team comes in.

Research Plan

For the year I spent with this lab, we used a variety of research methodologies to collect data about the novel compounds being developed. To maintain confidentiality of generated data, any identifying information has been omitted. Our chosen rat model was the Sprague Dawley rat as they have been recognized as they have been shown to be ideal for safety and efficacy testing.

Conditioned Place Preference (CPP)

The CPP method is a form of Pavlovian conditioning to test the motivational effects of objects and experiences, in this case our drug. By measuring the time spent in the chamber in which the rats were dosed, we could infer the rats’ affinity for the stimulus associated with that side of the chamber.

Each week, we ran three CPP studies consisting of five rats each. The first two days consisted of getting the rats (control and drug group) acclimatized to the CPP chambers followed by the third and fourth days in which the control groups received saline and the drug group received compound. On the fifth and final day, rats weren’t dosed and allowed to roam as they pleased. Each day of the study involved an hour of CPP chamber time for the rats in which data was collected by top and side cameras in the chambers.

Hot Plate

Novel compounds were tested for analgesic effects on the hot plate assay. We were constantly testing the effects of various compounds each week, sometimes running over 30 rats through the assay. The first four days of the assay consisted of acclimatizing the rats to hot plates at different timepoints after being dosed with saline. On the test date, animals were dosed with compound and placed atop the hot plates at various timepoints. Each day, the animals were timed for reaction to the hot plate.

Respiratory Depression

Respiratory was one of the most important assays to run as it this mostly had to do with the drug’s safety. Each week, about five to six animals were tested in the whole body plethysmometer (WBP) chambers. Relying on air pressure measurements to monitor the animals’ breath rates, these devices help scientists to visualize changes in breath rate and volume. For two days, animals would sit in these chambers for four hours each so that we could record their baseline breath rates. On the third day, animals would be dosed either: A) with opioids to measure the baseline breath rate when drugged or B) with opioids followed by our rescue drug 20 minutes post-dose to measure the recovery of breath rates. As an intensive study requiring strong amounts of focus, this study was delegated to me to lead.

Marble Burying

Introduced in the latter half of my time on the team, the marble burying assay was used to assess drug-induced anxiety in the animals. Considered a lower priority assay, we ran these only against compounds that were deemed more successful as a result of the above assays. Ten animals were tested for each promising compound (five control and five study groups) and the average number of marbles displaced/buried per group was recorded. The idea here was to measure the irritability of animals dosed with different compounds as an analog for human clinical trials.

Constraints

With a small team of three in the in-vivo behavioral pharmacology team, each of us had to balance the studies we led along with the ongoing studies that were to be run (hot plate, CPP, etc.). In the end, this workload proved useful to my future in putting my time management skills to the test. Working in an entirely different city than the medicinal chemistry team (based in South San Francisco, CA) also had its challenges as immediate communication wasn’t always possible.

As mentioned above, sharing a research facility and campus with the world’s largest wind tunnel also proved difficult. Wind tunnel and rocket engine tests weren’t always announced, so assays being run during those tests ultimately needed to be scrapped and started over on other days.

Findings

The in-vivo behavioral pharmacology and medicinal chemistry teams worked in collaboration to narrow down the molecular structure of our more promising compounds in order to hone in on an ideal drug that could be used in clinical trials. The data collected by our team allowed us to convey improvements and limitations of each iteration of the compounds to the medicinal chemistry team. In my time at the laboratory, we were close. Prior to my layoff due to re-organization and budgetary constraints, the data yielded by all our assays proved promising and we were ever on the brink of coming up with the ideal combination of analgesic and drug antagonist (displacing opioids from the opioid receptor).

Communicating Findings

At the end of each assay, data was compiled on Microsoft Excel files and immediately routed to the medicinal chemistry teams. As a result, data on our compounds were flowing daily from our team while the medicinal chemists worked to improve the molecular structures of our compounds. Neither team was a rate limiting factor as they just as often sent updated/modified compounds back to our team based on the previous week’s data. This allowed both teams to work smoothly in conjunction, barely stopping for any reason.

Every other month, the researchers from our team went to the offices in South San Francisco to present any major findings in our scientist and board meetings. This was vital in keeping everyone in the loop on the company’s general direction and to build rapport between departments.

Next Steps

Since my departure from the research team at the NASA Ames Research Center, I had contributed my behavioral pharmacology expertise to the projects at other companies. However, moving forward with the opioid use disorder research studies here, the next steps would be to continue fine-tuning the various assays being run by bringing timepoints closer to each other to more closely mark progress of pharmacological effects over time and determine the perfect combination of analgesics, recovery time, and dose time post-induction of opioid addiction in the animals. The result of future efforts could yield the next new rescue drug and improve the lives of people addicted to opioids as well as the lives of their friends and families.