Botulinum toxin injections could be a powerful tool for treating post-amputation pain

Botulinum toxin injections provided greater short-term relief for phantom limb pain than standard medical and surgical care among Ukrainian war amputees, reports a new study led by Northwestern Medicine and Ukrainian physicians.

The study, which involved 160 amputees treated at two hospitals in western Ukraine between 2022 and 2024, could ultimately benefit millions worldwide, according to the research team.

Post-amputation pain affects most amputees. The condition limits prosthetic use, mobility and quality of life. In the U.S., more than 2 million people live with limb loss. In Ukraine, it is estimated that over 100,000 soldiers and civilians have lost limbs since Russia's full-scale invasion, which began in 2022.

Botulinum toxin injected into painful stumps of residual limbs and around neuromas was on some outcome measures more effective than comprehensive medical and surgical treatment at one month post-treatment."

Dr. Steven P. Cohen, senior study author, professor of anesthesiology and the vice chair of research and pain medicine, Northwestern University Feinberg School of Medicine

"Our results show that botulinum toxin potentially could be a powerful short-term tool for treating post-amputation pain when used alongside comprehensive medical and surgical care," said co-author Dr. Roman Smolynets, an anesthesiologist and intensive care specialist at Multidisciplinary Clinical Hospital of Emergency and Intensive Care in Lviv, Ukraine.

"It could be another step toward helping amputees live with less pain and more dignity. But always as an additional point to comprehensive medical and surgical care, not as a monotherapy."

The study will publish on Oct. 21 in the journal Archives of Physical Medicine and Rehabilitation.

The findings

All study participants were amputees treated at the First Medical Union of Lviv or Ivano-Frankivsk Regional Hospital. About one-fifth received botulinum toxin injections around painful nerve endings, called neuromas, in addition to standard medical and physical therapy. The other participants received comprehensive medical and surgical treatment, which included surgical revision, nerve blocks, physical and psychological therapy, medications and other interventional procedures.

The research team assessed pain levels at the start of treatment and after one and three months, focusing separately on phantom limb pain (pain in the missing limb) and residual limb pain (pain at the stump site).

At one month, the botulinum toxin group experienced an average reduction of four points in phantom limb pain on a 10-point scale, compared with just one point among patients in the comparison group. Also at one month, 69% of patients who received botulinum toxin achieved a meaningful improvement (defined as at least a 30% drop in pain) in phantom limb pain, versus only 43% in the other patient group.

However, the results shifted at three months: Patients who received comprehensive care showed more durable pain relief than the botulinum toxin group, consistent with previous research showing that botulinum toxin's pain-relieving effects typically last about three months.

A novel way to inject botulinum toxin

While botulinum toxin injections, a non-surgical treatment that alleviates pain by blocking nerve signals, are most commonly known for their use in cosmetic procedures, they are also an established tool to treat chronic pain.

In the study, the substance was injected in a novel way. The research team used ultrasound guidance to inject botulinum toxin directly around painful nerve endings and surrounding soft tissues, rather than into muscle or skin. This targeted "peri-neuromal" approach, the scientists believe, may explain the strong short-term reduction in pain by quieting nerve activity and local inflammation. Previous studies have shown botulinum toxin to be effective for neuropathic pain, but none injected it around painful nerves.

The new findings suggest that botulinum toxin injections near nerves may also help relieve other types of nerve pain, such as shingles-related pain, carpal tunnel syndrome and pain following surgeries like mastectomy or thoracotomy.

A friendship with a Ukrainian anesthesiologist

Cohen, who traveled to Ukraine in 2024 to help launch the study, is a retired U.S. Army colonel who served four overseas tours in support of military operations; his son currently serves with the infantry.

In Ukraine, he partnered with Smolynets, who has treated thousands of soldiers and civilians injured in the war by working in the country's largest trauma and emergency center, and Dr. Nadiya Segin, who is pioneering the use of Botulinum toxin and nerve stimulation to treat war injuries.

Smolynets will visit Chicago the week of Oct. 19 with a Ukrainian delegation for an observership program, spending time with Cohen at his pain medicine clinic and at a Shirley Ryan AbilityLab in downtown Chicago. The two physicians, now close friends, are available for interviews during that week.

More research in Ukraine

Cohen and his colleagues stress the need for larger, randomized trials to confirm their findings, refine patient selection and optimize botulinum toxin dosing. Future research should also explore whether repeat botulinum toxin injections over time could produce sustained benefits for post-amputation pain, as they appear to do for migraine treatment.

Cohen and Smolynets, who published another study in February about using hydrodissection for post-amputation pain in Ukraine, are also researching more novel war treatments in Ukraine, at Walter Reed, and Northwestern, for traumatic brain injury and PTSD. These studies are underway. 

"As a retired colonel and the father of an infantry soldier who could be deployed in future conflicts and suffered from traumatic brain injury while at the U.S. Military Academy, this research carries special personal meaning for me," Cohen said.

The study is titled "Peri-Neuromal Botulinum Toxin Injection for War-Related Postamputation Pain: A Pragmatic, Multicenter, Comparative-Effectiveness Study." It was partially funded by the U.S. Department of Defense (via the Department of Physical Medicine & Rehabilitation at Uniformed Services University) and the ASPEN Medical Foundation.