Cryoanalgesia for Phantom Limb Pain

Overseen By Brian Ilfeld, MD, MS

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of California, San Diego

Disqualifiers: Allergy to anesthetics, pregnancy, incarceration, morbid obesity, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

12 Participants Needed

Trial Summary

What is the purpose of this trial?

When a limb is severed, pain perceived in the part of the body that no longer exists often develops and is called "phantom limb" pain. Unfortunately, phantom pain goes away in only 16% of afflicted individuals, and there is currently no reliable definitive treatment. The exact reason that phantom limb pain occurs is unclear, but when a nerve is cut-as happens with an amputation-changes occur in the brain and spinal cord that actually increase with worsening phantom pain. These abnormal changes may often be corrected by putting local anesthetic-called a "nerve block"-on the injured nerve, effectively keeping any "bad signals" from reaching the brain with a simultaneous resolution of the phantom limb pain. However, when the nerve block resolves after a few hours, the phantom pain returns. But, this demonstrates that the brain abnormalities-and phantom pain-that occur with an amputation are not necessarily fixed, and may be dependent upon the "bad" signals being sent from the injured nerve(s), suggesting that a very long peripheral nerve block-lasting many months rather than hours-may permanently reverse the abnormal changes in the brain, and provide definitive relief from phantom pain. A prolonged nerve block lasting a few months may be provided by freezing the nerve using a process called "cryoneurolysis". The ultimate objective of the proposed research study is to determine if cryoanalgesia is an effective treatment for intractable post-amputation phantom limb pain. The proposed pilot study will include subjects with an existing above-knee amputation who experience intractable daily phantom limb pain. A single ultrasound-guided treatment of cryoneurolysis (or sham block-determined randomly like a flip of a coin) will be applied to the major nerves of the thigh. Although not required, each subject may return 4-6 months later for the alternative treatment (if the first treatment is sham, then the second treatment would be cryoneurolysis) so that all participants have the option of receiving the active treatment. Subjects will be followed for a total of 12 months with data collected by telephone.

Will I have to stop taking my current medications?

You will need to keep your current pain medication routine the same from one month before to at least four months after the initial procedure.

What data supports the effectiveness of the treatment Cryoneurolysis for Phantom Limb Pain?

Research shows that cryoneurolysis, which uses extreme cold to temporarily block nerve pain, has been effective in reducing pain after limb amputation and mastectomy. In a case series, patients reported significant pain relief after limb amputation without ongoing phantom pain, and a multicenter trial found that a single treatment reduced phantom pain months later. ^{1 2 3 4 5}

Is cryoanalgesia safe for humans?

Cryoanalgesia, also known as cryoneurolysis, is generally considered safe with minimal risk of complications when performed using imaging guidance. Studies have shown that it provides pain relief without causing serious side effects or irreversible nerve damage. ^{1 2 4 6 7}

How is cryoneurolysis different from other treatments for phantom limb pain?

Cryoneurolysis is unique because it uses extreme cold to temporarily interrupt nerve signals without causing permanent nerve damage, offering pain relief without the risks associated with opioids or the need for open surgery. It is minimally invasive and guided by imaging techniques like ultrasound, making it a safer and more precise option compared to traditional methods. ^{1 2 4 8 9}

Research Team

Brian Ilfeld, MD

Principal Investigator

University of California, San Diego

Eligibility Criteria

This trial is for adults over 18 who have had an above-knee amputation at least 12 weeks ago and suffer from moderate to severe phantom limb pain daily. Participants should not change their pain medication or undergo elective surgeries from one month before until four months after the initial treatment.

Inclusion Criteria

I had a leg amputation above the knee more than 12 weeks ago.

I experience daily phantom limb pain rated 4 or higher for the last 2 months.

I agree not to change my pain medication or have elective surgery for 5 months around my cryoneurolysis procedure.

Exclusion Criteria

My BMI is over 40.

You are currently in jail or prison.

Pregnancy

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Initial Treatment

Participants receive either cryoneurolysis or sham procedure on the major nerves of the thigh

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Data collected by telephone

Optional Crossover Treatment

Participants may opt for a crossover treatment with the alternative procedure (either active cryoneurolysis or sham)

4-6 months after initial treatment

1 visit (in-person)

Treatment Details

Interventions

• Cryoneurolysis

Trial Overview The study tests cryoanalgesia, a prolonged nerve block achieved by freezing nerves, against a sham procedure to see if it can provide long-term relief from phantom limb pain in individuals with above-knee amputations. Each participant may receive both treatments over the course of the study.

Participant Groups

Group I: Sham Comparator first, then optional cryoneurolysis treatment Experimental Treatment 2 Interventions

Initial treatment: Sham cryoneurolysis of the major nerves of the thigh in the residual limb: The cryoneurolysis device will be triggered using 1 cycle of 5.5-minute argon activation followed by a 30-60 second defrost period with helium (Varian) or 2 cycles of 2-minute gas activation with a sham probe separated by a 30-60 second defrost (Epimed). However, for sham treatment, the gas is NOT deployed to the probe tip and therefore there is NO drop in temperature with NO resulting cryoneurolysis. Optional active crossover treatment: Cryoneurolysis of the major nerves of the thigh in the residual limb: The cryoneurolysis device will be triggered using 1 cycle of 5.5-minute argon activation followed by a 30-60 second defrost period with helium (Varian) or 2 cycles of 2-minute gas activation with an active probe separated by a 30-60 second defrost (Epimed). For active treatment, the gas will be deployed to the probe tip where a drop in temperature will result in cryoneurolysis.

Group II: Cryoneurolysis first, then optional sham crossover treatment Experimental Treatment 2 Interventions

Initial treatment: Cryoneurolysis of the major nerves of the thigh in the residual limb: The cryoneurolysis device will be triggered using 1 cycle of 5.5-minute argon activation followed by a 30-60 second defrost with helium (Varian) or 2 cycles of 2-minute gas activation with an active probe separated by a 30-60 second defrost (Epimed). For active treatment, the gas will be deployed to the probe tip where a drop in temperature will result in cryoneurolysis. Optional sham crossover treatment: Sham cryoneurolysis of the major nerves of the thigh in the residual limb: The cryoneurolysis device will be triggered using 1 cycle of 5.5-minute argon activation followed by a 30-60 second defrost period with helium (Varian) or 2 cycles of 2-minute gas activation with a sham probe separated by a 30-60 second defrost (Epimed). However, for sham treatment, the gas is NOT deployed to the probe tip and therefore there is NO drop in temperature with NO resulting cryoneurolysis.

Cryoneurolysis is already approved in United States for the following indications:

Approved in United States as Cryoneurolysis for:

• Pain management for traumatic rib fractures
• Postoperative pain relief

Who Is Running the Clinical Trial?

University of California, San Diego

Lead Sponsor

Trials

1,215

Recruited

1,593,000+

Epimed International

Collaborator

Trials

2

Recruited

110+

Varian Medical Systems

Industry Sponsor

Trials

63

Recruited

3,700+

Dow R. Wilson

Varian Medical Systems

Chief Executive Officer since 2012

MBA from Dartmouth's Amos Tuck School of Business, BA from Brigham Young University

Dr. Deepak Khuntia

Varian Medical Systems

Chief Medical Officer since 2020

MD from the University of Cambridge, PhD from the University of Leicester

Findings from Research

In three cases of limb amputation, ultrasound-guided percutaneous cryoneurolysis provided effective pain relief in the immediate postoperative period without leading to persistent postsurgical or phantom limb pain.

The procedure was safe, with no reported adverse events, suggesting that cryoneurolysis could be a promising alternative to traditional local anesthetic techniques for managing post-amputation pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ultrasound-Guided Percutaneous Cryoneurolysis for Postoperative Analgesia After Limb Amputation: A Case Series. Gabriel, RA., Finneran, JJ., Trescot, AM., et al.[2021]

Ultrasound-guided percutaneous cryoneurolysis significantly reduced pain levels on postoperative day 2 after mastectomy, with active treatment participants reporting a median pain score of 0 compared to 3 in the sham group (P < 0.001).

The technique also led to a dramatic reduction in opioid use during the first three weeks post-surgery, with the active group using only 1.5 mg of oxycodone compared to 72 mg in the sham group, and resulted in lower rates of chronic pain after one year (3% in active vs 17% in sham, P < 0.001).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preoperative Ultrasound-guided Percutaneous Cryoneurolysis for the Treatment of Pain after Mastectomy: A Randomized, Participant- and Observer-masked, Sham-controlled Study. Ilfeld, BM., Finneran, JJ., Swisher, MW., et al.[2023]

A study involving 144 patients with lower-limb amputations found that cryoneurolysis did not significantly reduce phantom pain intensity compared to a sham treatment after 4 months, indicating limited efficacy for this intervention.

One serious adverse event occurred due to a protocol deviation, highlighting potential safety concerns associated with the procedure, particularly if not performed correctly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ultrasound-guided Percutaneous Cryoneurolysis to Treat Chronic Postamputation Phantom Limb Pain: A Multicenter Randomized Controlled Trial. Ilfeld, BM., Smith, CR., Turan, A., et al.[2023]

Cryoanalgesia, or cryoneurolysis, is a safe and effective method for relieving pain by applying extreme cold to peripheral nerves, interrupting pain signals without causing permanent nerve damage.

This technique, guided by imaging methods like ultrasound or CT, offers a minimally invasive alternative to traditional pain management approaches, especially important in the context of the opioid crisis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Percutaneous cryoanalgesia for pain palliation: Current status and future trends. Filippiadis, D., Efthymiou, E., Tsochatzis, A., et al.[2021]

In a pilot study involving 21 patients with refractory phantom limb pain, image-guided percutaneous nerve cryoablation demonstrated a 100% technical success rate and was found to be a feasible and safe procedure.

Patients experienced significant reductions in pain intensity, from a mean score of 6.2 to 2.0, and improvements in disability scores, from 11.3 to 3.3, indicating that this treatment may be an effective option for managing phantom limb pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Percutaneous Image-Guided Cryoablation for the Treatment of Phantom Limb Pain in Amputees: A Pilot Study. Prologo, JD., Gilliland, CA., Miller, M., et al.[2022]

Ultrasound guidance during cryoneurolysis allows for real-time monitoring of needle placement, leading to more accurate targeting of peripheral nerves and improved outcomes in pain relief.

Patients have reported varying degrees of long-term pain relief and functional improvement from cryoneurolysis, with no serious complications noted, suggesting it is a safe alternative to other pain management techniques.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ultrasound-Guided Cryoanalgesia of Peripheral Nerve Lesions. Djebbar, S., Rossi, IM., Adler, RS.[2017]

Image-guided percutaneous intercostal nerve cryoablation, using cone-beam computed tomography and software-assisted planning, is a feasible method for treating chronic post-thoracotomy pain syndrome (PTPS).

In a case study, this technique provided approximately 8 weeks of significant pain relief for a patient suffering from intractable PTPS, suggesting it may be a valuable option for managing this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Image-guided nerve cryoablation for post-thoracotomy pain syndrome. Koethe, Y., Mannes, AJ., Wood, BJ.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Ultrasound-Guided Percutaneous Cryoneurolysis for Postoperative Analgesia After Limb Amputation: A Case Series. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Preoperative Ultrasound-guided Percutaneous Cryoneurolysis for the Treatment of Pain after Mastectomy: A Randomized, Participant- and Observer-masked, Sham-controlled Study. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Ultrasound-guided Percutaneous Cryoneurolysis to Treat Chronic Postamputation Phantom Limb Pain: A Multicenter Randomized Controlled Trial. [2023]

4. France pubmed.ncbi.nlm.nih.gov

Percutaneous cryoanalgesia for pain palliation: Current status and future trends. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Percutaneous Image-Guided Cryoablation for the Treatment of Phantom Limb Pain in Amputees: A Pilot Study. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Ultrasound-Guided Cryoanalgesia of Peripheral Nerve Lesions. [2017]

7. United States pubmed.ncbi.nlm.nih.gov

The applications of cryoneurolysis for acute and chronic pain management. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Cryoanalgesia: Review with Respect to Peripheral Nerve. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Image-guided nerve cryoablation for post-thoracotomy pain syndrome. [2021]