Designing Alternatives to Morphine After Surgery

Surgical procedures can be lifesaving for many, but they often come with a major drawback: post-operative pain. In the hospital after surgery, many patients are given morphine, a powerful opioid pain reliever. Morphine can be provided via an intravenous pump controlled by the patient.

When departing the hospital or clinic, many patients are then given a prescription for opioid pills. For some people, this prescription can be the beginning of opioid misuse and the risk of developing an opioid use disorder. Finding morphine alternatives may help prevent addiction from taking hold.

Serina Therapeutics, Inc., a small company in Huntsville, Alabama, is studying whether the medication buprenorphine could be used as an alternative to post-surgical morphine. The research is part of the Helping to End Addiction Long-term^® Initiative, or NIH HEAL Initiative^®, which seeks to combat the opioid epidemic by addressing both opioid use disorder and pain. Serina’s research is part of the initiative’s research program to create new, non-addictive treatments for pain.

Buprenorphine is currently used to treat both opioid use disorder and chronic pain. One version of buprenorphine is available for post-surgical pain, but it is hardly ever used because it must be given every six hours via a painful injection into muscle.

Buprenorphine works similarly to morphine, and it can also be misused. But, because it is less powerful and addictive than morphine, the company’s scientists and medical advisors think it is a safer medication for post-surgical pain — if they can find a better way to administer it.

The Serina team is working on a way to deliver buprenorphine as a single injection that would offer several days of pain relief. The new technique delivers multiple days’ supply of medication all at once — packaged in such a way that the body’s own tools will release buprenorphine molecules at a measured pace over a period of time.

A new polymer

The new technology is a polymer called poly(2-oxazoline) — POZ for short. A polymer is another name for a long string of the same molecule linked together. POZ with buprenorphine consists of many copies of the medication attached via chemical bonds, like individual bulbs on a string of lights. POZ with buprenorphine will be injected under the skin — less painful than an injection into muscle. Once it is in the blood, a naturally occurring enzyme in the body snips off the buprenorphine molecules slowly over a period of four to five days. This allows for controlled release of the drug.

POZ is similar to polyethylene glycol, or PEG: a polymer that works in a similar way that is used in more than a dozen medications approved by the FDA. For example, PEGylated interferon is used to treat chronic hepatitis.

According to co-founders of Serina Therapeutics Tacey Viegas, Ph.D., and Randall Moreadith, M.D., Ph.D., POZ is expected to be easier to use than PEG and cause fewer immune reactions. The two scientists had worked with PEG before co-founding Serina.

The road to buprenorphine

Buprenorphine is one of several medications the Serina team is working with. The medication they started with was a POZ version of rotigotine, a medication for Parkinson’s disease.

“For Parkinson’s, you often take drugs three or four times a day,” Moreadith says. For people with this movement disorder, missing a dose is a problem because medication must stay at a particular level in the blood to control symptoms such as tremors, stiffness, and loss of balance.

In the first clinical study of POZ with rotigotine, in a small group of Parkinson’s patients, the new formulation released rotigotine continuously and safely. Now it is being tested in patients who have early-stage Parkinson’s disease or a condition known as restless legs syndrome to see how well it works.

With success so far on that first drug, the Serina team went looking for other medications with the chemical properties that make it possible to attach them to POZ. That is how they identified buprenorphine, which has been FDA-approved for nearly 40 years.

Buprenorphine is an opioid medication less powerful than morphine but effective for pain relief in many patients. Buprenorphine works as a treatment for opioid use disorder by binding tightly to opioid receptors in the brain, preventing other opioids like heroin from interacting with these receptors and causing rewarding effects like euphoria. It is less likely to cause a high than morphine, but it can be just as effective at pain relief.

The Serina scientists propose that a POZ with buprenorphine injection would be given once while a patient is waking up from surgery in the recovery room and work for about four days — enough to get them past the worst of the pain, explains Moreadith.

If the POZ system works as planned, buprenorphine levels in the blood would stay consistent and the leftover polymer will safely leave the body in urine. Having gotten past those first few days after surgery, patients could be sent home with instructions to use non-addictive pain medications, such as many sold over the counter.

How the NIH HEAL Initiative is helping

Funding from the NIH HEAL Initiative is enabling the Serina Therapeutics team to prepare an Investigational New Drug application (IND), which is required by the FDA before human trials of a new medication can begin. This funding is supporting the team’s work to test POZ with buprenorphine in rodents and monkeys, show that they can produce the medication safely, and then design the human studies.

The company hopes to be able to submit the IND application in 2021, and if given permission by the FDA, begin trials in humans. First the drug will be tested for safety in healthy research participants. If it is safe, it will then be tested in people who have undergone a bunionectomy, a painful foot surgery, before broadening the research to testing in patients who have had major surgeries.

The initiative’s support is a Small Business Innovation Research (SBIR) grant. This kind of funding allows small companies like Serina Therapeutics to take steps toward commercializing their products. The NIH HEAL Initiative is also funding several other small companies that are developing alternative approaches to pain or opioid use disorder, such as a human-on-a-chip model of overdose, an innovative dental adhesive, and virtual reality psychotherapy for chronic pain.