hree decades-old antibiotics administered together can block a type of pain triggered by nerve damage in an animal model, UT Southwestern researchers report.
The finding, published online today in PNAS, could offer an alternative to opioid-based painkillers, addictive prescription medications that are responsible for an epidemic of abuse in the U.S.
Over 100 million Americans are affected by chronic pain, and a quarter of these experience pain on a daily basis, a burden that costs an estimated $600 billion in lost wages and medical expenses each year.
For many of these patients – those with cancer, diabetes, or trauma, for example – their pain is neuropathic, meaning it’s caused by damage to pain-sensing nerves.
To treat chronic pain, prescriptions for opioid painkillers have increased exponentially since the late 1990s, leading to a rise in abuse and overdoses. Despite the desperate need for safer pain medications, development of a new prescription drug typically takes over a decade and more than $2 billion according to a study by the Tufts Center for the Study of Drug Development, explains study leader Enas S. Kandil, M.D., associate professor of anesthesiology and pain management at UTSW.
Seeking an alternative to opioids, Kandil and her UT Southwestern colleagues – including Hesham A. Sadek, M.D., Ph.D., professor of internal medicine, molecular biology, and biophysics; Mark Henkemeyer, Ph.D., professor of neuroscience; Mahmoud S. Ahmed, Ph.D., instructor of internal medicine; and Ping Wang, Ph.D., a postdoctoral researche – explored the potential of drugs already approved by the Food and Drug Administration (FDA).
The team focused on EphB1, a protein found on the surface of nerve cells, which Henkemeyer and his colleagues discovered during his postdoctoral training nearly three decades ago. Research has shown that this protein is key for producing neuropathic pain. Mice genetically altered to remove all EphB1 don’t feel neuropathic pain, he explains. Even mice with half the usual amount of this protein are resistant to neuropathic pain, suggesting EphB1’s promise as a target for pain-relieving drugs. Unfortunately, no known drugs inactivate EphB1.
Exploring this angle further, Ahmed used computer modeling to scan a library of FDA-approved drugs, testing if their molecular structures had the right shape and chemistry to bind to EphB1. Their search turned up three tetracyclines, members of a family of antibiotics used since the 1970s.
These drugs – demeclocycline, chlortetracycline, and minocycline – have a long history of safe use and minimal side effects, Ahmed says.
To investigate whether these drugs could bind to and inactivate EphB1, the team combined the protein and these drugs in petri dishes and measured EphB1’s activity. Sure enough, each of these drugs inhibited the protein at relatively low doses.
Using X-ray crystallography, Wang imaged the structure of EphB1 with chlortetracycline, showing that the drug fits neatly into a pocket in the protein’s catalytic domain, a key portion necessary for EphB1 to function.
In three different mouse models of neuropathic pain, injections of these three drugs in combination significantly blunted reactions to painful stimuli such as heat or pressure, with the triplet achieving a greater effect at lower doses than each drug individually. When the researchers examined the brains and spinal cords of these animals, they confirmed that EphB1 on the cells of these tissues had been inactivated, the probable cause for their pain resistance.
A combination of these drugs might be able to blunt pain in humans too, the next stage for this research, says Kandil.
“Unless we find alternatives to opioids for chronic pain, we will continue to see a spiral in the opioid epidemic,” she says.
“This study shows what can happen if you bring together scientists and physicians with different experience from different backgrounds. We’re opening the window to something new.”
Written by Hope Cristol; Reviewed by Steven Richeimer, MDPeer ReviewedPhysicians who treat severe back pain stand at a challenging juncture in medicine. Opioids continue to be the most powerful pain killers available, yet they provide insufficient relief in the context of several pain conditions. The opioid crisis also causes many to feel conflicted about prescribing drugs to patients. Among many data points: 10.3 million people misused prescription opioids in 2018 alone, according to a national survey from the Substance Abuse and Mental Health Services Administration.
Pain expert Steven Richeimer, MD, believes ketamine should be more widely used as an alternative to opioids. Research has shown that in controlled doses and environments, ketamine can play an important role in human pain management.
Dr. Richeimer is Chief, Division of Pain Medicine and Professor of Anesthesiology & Psychiatry at the University of Southern California Keck School of Medicine. He recently prepared a lecture on this topic for the California Society of Anesthesiologists annual medical conference in April. Although the conference was canceled due to COVID-19 concerns, Dr. Richeimer graciously shared some of his lecture’s key takeaways with SpineUniverse.
Ketamine is an NMDA receptor antagonist, along with several other commercially available drugs including memantine, amantadine, and dextromethorphan. Ketamine is an old drug: synthesized in 1962, approved by the U.S. Food and Drug Administration (FDA) in 1970, and used as a field anesthetic during the war in Vietnam. It is still widely used as an anesthetic in human and veterinary practice, but it has gained notoriety as a recreational drug for its potentially dissociative effects.
How Ketamine Relieves Pain
There are several mechanisms by which ketamine may mitigate pain. Research suggests it can:
- Reduce central sensitization
- Reduce opioid-induced hyperalgesia
- Reduce opioid tolerance
- Inhibit serotonin and dopamine reuptake
- Reduce pain-induced depression
Ketamine in Current Medical Practice
Ketamine, in low doses, may be used postoperatively to reduce opioid use and decrease nausea and vomiting. In some cases it provides primary postop pain relief, particularly in patients who do not tolerate opioids.
Ketamine is also administered in infusion centers for patients with intractable pain from several conditions, including:
- Chronic regional pain syndrome
- Other neuropathic conditions
- Refractory headache
Oral ketamine can be prescribed for pain management, but it is not commercially available; prescriptions must be sent to compounding pharmacies. Physicians who have not previously prescribed ketamine may want to work with a pain management specialist who is familiar with the drug.
Risks and Considerations
All drugs, particularly powerful pain relievers, come with a long list of potential side effects. Ketamine is no exception, and therefore should be avoided in patients with:
- Severe cerebrovascular and cardiovascular diseases
- Psychosis or delirium
- Severe liver disease / hepatitis
- Active substance abuse
- Glaucoma / increased intraocular pressure
- Hyperthyroidism or pheochromocytoma
Other Promising Opioid Alternatives
NMDA receptor antagonists, not just ketamine, are being studied for their potential role as opioid alternatives. They increase dopamine release and block dopamine reuptake, which can confer numerous benefits in a range of conditions.
Consider amantadine, originally approved by the FDA in 1966 as an antiviral. It was later found to be useful in Parkinson’s disease treatment and as an analgesic in veterinary practice.
Research published in Pain Medicine found that in young adults undergoing elective spine surgery, amantadine reduced fentanyl use during the procedure, reduced postoperative pain, and decreased morphine consumption.
Memantine, first synthesized in 1968, is FDA-approved to treat Alzheimer’s disease. It may improve memory, attention, language, and other systems affected by this form of dementia. Early research also suggests it may have a role in neuropathic pain – including mastectomy-related pain.
More information: Mahmoud S. Ahmed el al., “Identification of tetracycline combinations as EphB1 tyrosine kinase inhibitors for treatment of neuropathic pain,” PNAS (2021). www.pnas.org/cgi/doi/10.1073/pnas.2016265118