Sevoflurane for Neurocognitive Effects Related to Pain and Anesthesia

(SENS Trial)

Overseen By Keith M Vogt, MD, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: Keith M. Vogt, MD, PhD

Must not be taking: Antidepressants, Antipsychotics, Antiepileptics, others

Disqualifiers: Pregnancy, Chronic pain, Neurologic, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 3

Duration: 1 day

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore how acute pain affects long-term memory and physical responses, with or without a low dose of sevoflurane, an anesthetic. Researchers will use brain imaging to observe any changes. The study involves two visits and does not require long-term follow-up. It suits generally healthy adults with normal hearing and memory who are free from chronic pain and other significant health issues. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking scientific knowledge.

Will I have to stop taking my current medications?

Yes, you may need to stop taking certain medications. The trial excludes people who regularly take medications like antidepressants, anti-anxiety drugs, and some others. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that sevoflurane, an inhaled anesthetic, is generally safe for short-term use. Studies have found it to be well-tolerated during surgeries. However, some research suggests that long-term or repeated use might affect memory and brain development, particularly in young children. For adults, these effects seem temporary.

In this trial, researchers use sevoflurane in small amounts during nerve stimulation. The trial does not include long-term follow-up and focuses on short-term effects. This approach helps reduce potential risks associated with longer exposure. Overall, using sevoflurane in controlled settings like this one is considered safe based on existing evidence. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about sevoflurane for neurocognitive effects related to pain and anesthesia because it offers a unique approach compared to traditional pain management methods, such as opioids or local anesthetics. Sevoflurane is an inhaled anesthetic, which means it can be precisely controlled and adjusted during procedures, potentially reducing cognitive side effects. Additionally, when paired with peripheral nerve stimulation, sevoflurane might help improve pain management and cognitive outcomes, offering a dual-action approach that isn't typical with standard treatments. This combination could lead to more efficient pain relief while minimizing negative impacts on the brain, a promising avenue in pain and anesthesia research.

What evidence suggests that this trial's treatments could be effective for neurocognitive effects related to pain and anesthesia?

Research shows that sevoflurane, an inhaled anesthetic, can affect memory and thinking in various ways. Some studies suggest it might cause memory problems, particularly in older individuals after surgery. Evidence indicates that people using sevoflurane may take longer to recover their cognitive skills compared to those using other anesthetics like propofol. However, researchers are still learning about its long-term effects on memory and its impact on pain response. In this trial, all participants will receive sevoflurane along with painful electric nerve stimulation to better understand these effects when sevoflurane is used in small amounts and in situations involving sudden pain. ^{1 6 7 8 9}

Who Is on the Research Team?

Keith M Vogt, MD, PhD

Principal Investigator

University of Pittsburgh

Are You a Good Fit for This Trial?

This trial is for healthy adults aged 18-59 with normal hearing, memory, and body weight. Participants must be native English speakers with at least a high school education, not pregnant, without chronic diseases or severe medical conditions like heart disease or seizures, and free from drug use including marijuana and heavy alcohol consumption.

Inclusion Criteria

Have none of the specific exclusion criteria

I have a working email and phone number.

Anticipate ability to participate in all visits required for the phase of the study in which they are enrolled

Exclusion Criteria

You are afraid of being in small, enclosed spaces.

You have had a bad reaction to anesthesia in the past.

You drink alcohol every day or drink a lot of alcohol. You have a history of drinking too much alcohol.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Baseline Assessment

Participants undergo baseline functional MRI scans without sevoflurane to assess brain activity during pain and memory tasks

1 day

1 visit (in-person)

Treatment

Participants receive sevoflurane and undergo functional MRI scans to assess the effects on pain processing and memory encoding

1 day

1 visit (in-person)

Follow-up

Participants are monitored for memory performance 24 hours post-learning experiment

1 day

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Peripheral Nerve Stimulation
• Sevoflurane

Trial Overview The study tests how acute pain affects long-term memory and physiological responses with/without low-dose sevoflurane anesthesia. It involves two visits with no long-term follow-up using functional MRI to examine brain activity related to these effects.

How Is the Trial Designed?

Group I: Sevoflurane+Pain Experimental Treatment 2 Interventions

Single-arm study. All subjects receive sevoflurane and painful electric nerve stimulation, as described in the interventions.

Who Is Running the Clinical Trial?

Keith M. Vogt, MD, PhD

Lead Sponsor

Trials

4

Recruited

230+

Keith M Vogt

Lead Sponsor

Trials

4

Recruited

210+

National Institute of General Medical Sciences (NIGMS)

Collaborator

Trials

315

Recruited

251,000+

Published Research Related to This Trial

Sevoflurane exposure in rats leads to increased neuroinflammation and cognitive dysfunction, as evidenced by activated microglia and elevated inflammatory markers in the hippocampus.

The study suggests that HCN2 channels play a crucial role in mediating the neuroinflammatory response to sevoflurane, indicating that targeting HCN2 could be a potential strategy for preventing perioperative neurocognitive disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PEX5R/Trip8b-HCN2 channel regulating neuroinflammation involved in perioperative neurocognitive disorders. Xu, F., Wang, Y., Han, L., et al.[2022]

Ultrasound-guided placement of peripheral nerve stimulation electrodes in cadaver specimens showed no gross nerve damage and allowed for precise positioning near the targeted nerves, indicating a safe method for potential clinical use.

Out of the three electrodes placed, only one showed significant migration after 21 hours of simulated activity, suggesting that the anchoring technology used may effectively minimize electrode movement during normal use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility of ultrasound-guided percutaneous placement of peripheral nerve stimulation electrodes and anchoring during simulated movement: part two, upper extremity. Huntoon, MA., Hoelzer, BC., Burgher, AH., et al.[2019]

A new training curriculum for Peripheral Nerve Stimulation (PNS) has been developed by a multidisciplinary task force to standardize education and improve proficiency in this effective treatment for chronic pain.

The curriculum includes defined milestones for learners at different levels (early, advanced, and practitioner) and covers essential skills such as professionalism, medical knowledge, and procedural skills, ensuring comprehensive training in PNS therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Educational Curriculum for Peripheral Nerve Stimulation Developed by the North American Neuromodulation Society. Kalia, H., Abd-Elsayed, A., Malinowski, M., et al.[2023]

In a study involving 66 young patients, the type of anesthesia (sevoflurane, desflurane, or propofol) did not significantly affect postoperative cognitive function, as measured by psychometric tests after surgery.

There was no significant change in inflammatory markers (S-100β, IL-6, TNF-α) related to cognitive status, suggesting that anesthesia does not induce systemic inflammation that impacts cognitive outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Anesthetic Agents on Cognitive Function and Peripheral Inflammatory Biomarkers in Young Patients Undergoing Surgery for Spine Disorders. Sahoo, AK., Panda, N., Sabharwal, P., et al.[2022]

In a study involving 21 aged male rats, low concentrations of sevoflurane (2%) resulted in worse cognitive function, as indicated by longer swimming latencies in the Morris water maze test compared to higher concentrations (4%).

The lower concentration of sevoflurane was also associated with a significant reduction in intact CA1 hippocampal neurons, suggesting that it may have a more harmful effect on spatial cognitive function and neuronal health in aged rats.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of Different Sevoflurane Concentrations on Postoperative Cognitive Function in Aged Rats. Yamamoto, N., Kimura, T., Niiyama, Y.[2023]

A multicenter trial is investigating the effectiveness of percutaneous peripheral nerve stimulation (PNS) in reducing postoperative pain and opioid use after orthopedic surgeries, with participants receiving either active stimulation or a sham treatment for 14 days.

If successful, percutaneous PNS could provide effective pain relief without the risks associated with opioids, such as addiction and overdose, potentially transforming how postoperative pain is managed in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ultrasound-Guided Percutaneous Peripheral Nerve Stimulation: A Pragmatic Effectiveness Trial of a Nonpharmacologic Alternative for the Treatment of Postoperative Pain. Ilfeld, BM., Gelfand, H., Dhanjal, S., et al.[2021]

In a retrospective study of 46 patients with painful nerve injuries, peripheral nerve stimulation (PNS) provided good pain relief (50% or more reduction) in 78% of cases over a follow-up period of 3 to 16 years.

The average pain intensity significantly decreased from a visual analog scale (VAS) score of 69 before surgery to 24 after PNS, indicating that PNS is an effective long-term treatment option for selected patients with isolated painful neuropathies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term peripheral nerve stimulation for painful nerve injuries. Eisenberg, E., Waisbrod, H., Gerbershagen, HU.[2019]

Ultrasound-guided percutaneous peripheral nerve stimulation (PNS) is a promising method for managing acute postoperative pain, offering advantages over traditional local anesthetic blocks by avoiding motor and sensory deficits.

PNS may help reduce opioid use after surgery, and while initial studies show its effectiveness, more large-scale randomized controlled trials are needed to confirm its benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute postoperative pain management with percutaneous peripheral nerve stimulation: the SPRINT neuromodulation system. Gabriel, RA., Ilfeld, BM.[2022]

Peripheral nerve stimulation (PNS) has strong evidence supporting its effectiveness for treating various pain conditions, including chronic migraines and failed back surgery syndrome, based on a systematic review of 20 randomized controlled trials and 33 observational studies.

Newer, less invasive technologies for electrode placement make PNS a promising option for managing complex pain disorders, but it should be used carefully as an adjunct treatment after proper patient evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence-Based Clinical Guidelines from the American Society of Pain and Neuroscience for the Use of Implantable Peripheral Nerve Stimulation in the Treatment of Chronic Pain. Strand, N., D'Souza, RS., Hagedorn, JM., et al.[2022]

In a multicenter study involving 66 participants undergoing various orthopedic surgeries, percutaneous peripheral nerve stimulation significantly reduced postoperative pain and opioid consumption compared to sham stimulation, with active stimulation resulting in a median opioid use of only 5 mg versus 48 mg in the sham group.

Patients receiving active stimulation reported lower average pain scores (1.1) compared to those receiving sham treatment (3.1), indicating that this technique effectively alleviates pain without systemic side effects during the first week after surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Percutaneous Peripheral Nerve Stimulation (Neuromodulation) for Postoperative Pain: A Randomized, Sham-controlled Pilot Study. Ilfeld, BM., Plunkett, A., Vijjeswarapu, AM., et al.[2022]

In a study involving rats, sevoflurane demonstrated significant neuroprotective effects against cognitive dysfunction induced by isoflurane, as measured by the Morris water test and various neurochemical parameters.

Sevoflurane's protective effects were linked to its ability to reduce inflammation and oxidative stress, evidenced by alterations in pro-inflammatory cytokines and antioxidant levels, as well as a decrease in caspase-3 activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuroprotective potential of sevoflurane against isoflurane induced cognitive dysfunction in rats via anti-inflammatory and antioxidant effect. Gong, Y., Kang, P., Wang, J., et al.[2023]

Exposure to 2.5% sevoflurane anesthesia leads to significant loss of basal forebrain cholinergic neurons (BFCNs) and results in impairments in spatial and fear memory, highlighting a potential mechanism for postoperative cognitive dysfunction.

Administering nerve growth factor (NGF) can prevent the loss of BFCNs and improve cognitive function in mice treated with sevoflurane, suggesting that NGF may be a therapeutic target to mitigate cognitive deficits associated with this anesthetic.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nerve growth factor metabolic dysfunction contributes to sevoflurane-induced cholinergic degeneration and cognitive impairments. Xiong, L., Duan, L., Xu, W., et al.[2020]

Peripheral nerve stimulation (PNS) shows level II evidence for effectively treating refractory peripheral nerve injury, with about two-thirds of patients experiencing at least 50% sustained pain relief, based on a systematic review of 102 studies.

PNS has a safety advantage over spinal cord stimulation, as it carries no risk of central cord injury, and adverse events are generally minor, making it a promising option for pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Peripheral Nerve Stimulation for Chronic Pain: A Systematic Review of Effectiveness and Safety. Helm, S., Shirsat, N., Calodney, A., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12161350/

Long-term impact of sevoflurane exposure on behavioural and ... This prospective cohort study aims to evaluate behavioural and neurocognitive outcomes in 200 preschool children aged 4–6 years (1:1 allocation)

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12401349/

Effects of sevoflurane inhalation anesthesia versus propofol ... Sevoflurane inhalation anesthesia can result in emotional abnormality and cognitive dysfunction in elderly rats undergoing abdominal surgery. ...

3. withpower.com withpower.com/trial/phase-1-amnesia-11-2023-43faa

Sevoflurane for Neurocognitive Effects Related to Pain and ... Research shows that peripheral nerve stimulation (PNS) is effective for managing chronic pain and has potential for reducing postoperative pain and opioid use.

4. sciencedirect.com sciencedirect.com/science/article/pii/S0007091218304604

Propofol compared with sevoflurane general anaesthesia ... The incidence of delayed neurocognitive recovery at 1 week was significantly lower in the propofol group [14.8% (28/189)] than in the sevoflurane group [23.2% ( ...

5. frontiersin.org frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2021.702231/full

Update on the Mechanism and Treatment of Sevoflurane ... Sevoflurane treatment may increase the incidence of postoperative cognitive dysfunction (POCD), and patients with POCD exhibit lower cognitive abilities than ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S0166432823000451

Long-term sevoflurane exposure resulted in temporary ... Our results suggest that one early prolonged sevoflurane-based general anesthesia can induce neuroapoptosis and learning and memory deficit transiently but not ...

7. journals.lww.com journals.lww.com/md-journal/fulltext/2025/08290/effects_of_sevoflurane_inhalation_anesthesia.92.aspx

Effects of sevoflurane inhalation anesthesia versus propofol Recently, clinical studies find that patients may suffer from cognitive impairment after anesthesia, and postoperative cognitive dysfunction ( ...

8. frontiersin.org frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2025.1646246/full

Deciphering sevoflurane-induced neurotoxicity Based on current evidence from animal studies, sevoflurane anesthesia has been demonstrated to exert detrimental effects on both early neurodevelopment in ...

9. nature.com nature.com/articles/s41598-025-85834-1

Repeated sevoflurane exposure causes hypomyelination ... Nonetheless, numerous studies have reported the adverse effects of sevoflurane exposure on development and aged brain, including cognitive ...