Making OnabotulinumtoxinA Treatment for Migraine Less Painful

A new randomized trial shows that remote electrical neuromodulation reduces procedural pain and post-procedural headache.

Sydney Stokes was so dizzy she had to lie down. In 2021, she was working on her graduate degree while battling chronic migraine when her neurologist prescribed onabotulinumtoxinA (Botox) injections as a migraine preventive. But the first procedure was not going well. Stokes recalled sharp pricks and popping sensations in her upper forehead and above her ear as she received more than 30 injections of onabotulinumtoxinA into her neck, face, and shoulders.

“I don’t do very well with pain,” Stokes said in an interview with Migraine Science Collaborative. A mix of pain and anxiety consistently brought her to the edge of blacking out. She’d go on to abandon onabotulinumtoxinA after three rounds of treatment.

Stokes’ experience is a common one – but some relief may be on the horizon. A new randomized, sham-controlled study suggests that remote electrical neuromodulation (REN) applied during onabotulinumtoxinA injections can reduce pain from this procedure in those with migraine.

The research, from first author Nan Cheng, University of California Irvine, US, and colleagues, found that people with migraine who received 10 minutes of REN prior to onabotulinumtoxinA injections reported a significant reduction in pain during the procedure. They were also less likely to develop a headache after the injections.

The study is “a good step forward” for treating procedural pain in migraine patients receiving onabotulinumtoxinA, said Hannah Shapiro, University of California San Francisco, US, in an interview with Migraine Science Collaborative. “Prior to this study, there really wasn’t a standard of care for how to address the pain and distress of patients during these procedures,” she said. This study “comprehensively starts to address that pain.” Shapiro penned an editorial on the study but was not involved with the research.

The study was published in the February 2026 issue of Headache, with the editorial appearing online in Headache on January 24, 2026.

A standard of care that faces challenges
OnabotulinumtoxinA is a common treatment option for preventing chronic migraine. However, patients like Stokes often experience pain and anxiety while receiving their injections, which can contribute to discontinuation of treatment.

OnabotulinumtoxinA first entered the migraine field when people receiving the injections for cosmetic purposes began reporting fewer headaches. Two 2010 trials, called PREEMPT 1 and PREEMPT 2, later showed that people with chronic migraine who received onabotulinumtoxinA injections to the head, neck, and shoulders every 12 weeks had fewer migraine and headache days compared to placebo or baseline.

Since then, more than a million people have received onabotulinumtoxinA for migraine, and the procedure has become part of the standard of care for treating chronic migraine. But those with migraine are often already sensitive in the neck, shoulder, and face – the exact areas targeted for onabotulinumtoxinA injections. This sensitivity contributes to pain and anxiety for people receiving the procedure.

“For patients who already have migraine or sensory sensitivity, that repeated stimulation can be overwhelming,” said Cheng.

While some patients tolerate the procedure, others report feeling a burning or stinging sensation from the injections. Pooled analyses have also found that up to 12% of patients developed headaches after the procedure.

Thus far, pain management techniques for onabotulinumtoxinA procedures aren’t readily available for many patients. Some clinicians recommend breathing techniques, listening to music, or talking with someone during the procedure to distract from the discomfort. Other providers suggest applying anesthetic cream or ice packs to numb the injection sites. But for the most part, these methods “are not universally implemented,” said Shapiro.

This matters, because those who experience pain either during or after receiving onabotulinumtoxinA injections are three times more likely to discontinue treatment.

Active REN versus a sham device
To begin addressing this, Cheng and her colleagues asked whether existing pain management methods could help migraine patients receiving onabotulinumtoxinA. The team decided to focus on REN, a US Food and Drug Administration (FDA)-cleared migraine preventive and acute treatment that uses electrical pulses to activate peripheral nerves, which then induces the body’s natural ability to inhibit pain. The treatment is delivered by a device strapped to the upper arm.

The researchers recruited 80 people with chronic migraine who were already receiving onabotulinumtoxinA. The trial ended early because of clear positive results, and so only 60 patients were included in the final analysis.

These participants, aged between 22 and 74 years old, rated their pain on a 0 to 100 scale before onabotulinumtoxinA injections so that their baseline pain levels could be determined, and then rated their pain again during and after the procedure. In addition, the day after the procedure, they reported whether they had developed post-procedural headache.

Participants received 10 minutes of REN stimulation prior to receiving onabotulinumtoxinA injections. The researchers also used a sham REN device as a placebo; this device looked like the active device but did not provide therapeutic stimulation. Each participant would receive the active REN and sham in randomized order.

The study’s primary outcome was procedural pain intensity, and secondary outcomes included post-procedural headache and adverse events.

Those who received active REN prior to onabotulinumtoxinA reported an average 15-point-lower pain score during the procedure, compared to baseline. They also reported a 19-point decrease in post-procedural pain, compared to baseline. The sham device did not reduce pain compared to baseline during or after onabotulinumtoxinA treatment.

Further, only 15% of the active REN group reported post-procedural headache, compared to 55% of those who received the sham device and 39% at baseline.

Feeling more comfortable
For Cheng, the results suggest that REN could be part of the toolbox for helping patients navigate procedural pain associated with onabotulinumtoxinA and other needle-based treatments.

“For certain people, using the device changed how tolerable the entire procedure felt,” she said. This could help more patients stick to onabotulinumtoxinA treatments, or at least make the procedure more comfortable, she said.

“Effective treatment doesn’t have to come at the expense of comfort,” said Cheng. “When we pay attention to patient experience and make small, thoughtful changes, it can make a real difference in how people engage with care and how they feel about continuing treatment.”

To Shapiro, the results are “pretty convincing.” She works with children and teens, and anxiety around injections is a major roadblock for patients considering onabotulinumtoxinA. A device that reduces procedural pain could help these kids navigate this procedure and even advocate for their needs, she said.

Stokes said she would consider using REN for pain management. She recently decided to try onabotulinumtoxinA again, on her neurologist’s advice. She still needs to lie down to receive the injections, but the experience is less painful now, mostly because her provider gets her most painful injections done first.

Still, “it kind of puts you on edge to have somebody sticking needles in your face,” she said.  “I feel like some device in general would be super helpful with these sorts of things.”

Freda Kreier is a science journalist based in Corvallis, Oregon.

References
Remote electrical neuromodulation for reducing procedural pain in patients with chronic migraine receiving onabotulinumtoxinA injections: A randomized sham-controlled study.
Cheng et al.
Headache. 2026 Feb;66(2):397-406.

Comfort matters: A new strategy to ease injection pain during headache treatment procedures.
Shapiro H.
Headache. 2026 Jan 24. Online ahead of print.

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