Post-Amputation Phantom Limb PainNCT03449667
Cryoanalgesia to Treat Post-Amputation Phantom Limb Pain: A Department of Defense Funded Multicenter Study
A study testing Cryoneurolysis in people with Post-Amputation Phantom Limb Pain, run by University of California, San Diego at 6 sites in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Post-Amputation Phantom Limb Pain
- What is being tested?
- Cryoneurolysis
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 144 participants
- Where
- 6 sitesUnited States
- Study dates
- 23 Mar 2018to 17 Mar 2022
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Adult patients of at least 18 years of age
- with a lower limb traumatic or surgical amputation at least 12 weeks prior to enrollment distal to the hip (femoral head remaining)
- who experience at least moderate phantom limb pain-defined as a 3 or higher on the Numeric Rating Scale (NRS; 0-10, 0= no pain; 10=worst imaginable pain)-at least daily for the previous 2 months.
- accepting of a cryoneurolysis procedure
- willing to avoid both changes to their analgesic regimen as well as elective surgical procedures from 1 month prior to and at least 4 months following the initial cryoneurolysis procedure.
Who cannot join
- allergy to amide local anesthetics
- pregnancy
- incarceration
- inability to communicate with the investigators
- morbid obesity (body mass index > 40 kg/m2)
- possessing any contraindication specific to cryoneurolysis such as a localized infection at the treatment site, cryoglobulinemia, cold urticaria and Reynaud's Syndrome.
Trial locations and contacts
6 sites in 1 country.
6 sites in 1 country
United States6 sites
Walter Reed National Military Medical Center
Bethesda, Maryland, 20889
Cleveland Clinic
Cleveland, Ohio, 44195
University of Florida
Gainesville, Florida, 32610
Veterans Affairs Palo Alto Health Care System
Palo Alto, California, 94304
University California San Diego
San Diego, California, 92103
Naval Medical Center San Diego (NMCSD)
San Diego, California, 92134
About this study
Official title: Cryoanalgesia to Treat Post-Amputation Phantom Limb Pain: A Multicenter, Randomized, Double-Masked, Placebo-Controlled, Definitive Human Subjects Clinical 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 research study will include subjects with an existing lower extremity 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 target nerve(s) involved with the phantom pain. Although not required, each subject may return four 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.
Read the detailed description
Subjects will be asked to make no changes to their analgesic regimen for at least 1 month prior to the cryoneurolysis procedure and continuing for 4 months until the measurement of the primary end point-for the duration of the study, all patients will be allowed to continue their pre-intervention analgesics. All subjects will have a peripheral intravenous catheter inserted, standard noninvasive monitors applied, and oxygen administered via a facemask or nasal cannula. Midazolam and fentanyl (IV) will be titrated for patient comfort. The specific nerves targeted will be the sciatic and femoral (or their distal branches). The potential cryoneurolysis sites will be cleansed with chlorhexidine gluconate and isopropyl alcohol. The target nerves will be identified in a transverse cross-sectional (short axis) view using ultrasound. A Tuohy-tip needle will be inserted beneath the ultrasound transducer and directed until the needle tip is immediately adjacent to the target nerve. Local anesthetic (1-3 mL, lidocaine 2%) will be injected. This will be repeated for the femoral nerve. Within 20 minutes of the second injection, the subject's limb pain level will be evaluated on the 0-10 NRS and if higher than at baseline prior to injection, the subject will NOT continue with treatment and their participation in the study will terminate upon discharge.
Treatment group assignment (randomization). Remaining subjects will be allocated to one of two possible treatments:
- cryoneurolysis
- sham cryoneurolysis (placebo control)
Randomization will be computer-generated and stratified by enrolling institution in randomly chosen block sizes. Cryoneurolysis probes are available that either (1) pass nitrous oxide to the tip inducing freezing temperatures; or, (2) vent the nitrous oxide at the base of the probe so that no gas reaches the probe tip, resulting in no temperature change (PainBlocker, Epimed, Farmers Branch, Texas). Importantly, these probes are indistinguishable in appearance. Unmasking will not occur until statistical analysis is complete.
Intervention. The potential cryoneurolysis sites will be again cleansed with chlorhexidine gluconate and isopropyl alcohol. With the same ultrasound transducer used to previously administer local anesthetic, the target nerve will again be identified in a transverse cross-sectional (short axis) view at or distal to the deposition of local anesthetic. A cryoneurolysis device (PainBlocker, Epimed, Farmers Branch, Texas) will be inserted with the appropriate randomization-designated probe (either active or sham/placebo) and nitrous oxide. The cryoneurolysis device will be triggered using 3 cycles of 2-minute gas activation (active or sham) separated by 1-minute defrost periods. The process will be repeated with the same treatment probe for the femoral nerve (e.g., both nerves will receive either active cryoneurolysis or sham/placebo, and not a mix of the two possible treatments).
Optional crossover treatment. Four to 6 months following the initial treatment, subjects may return for an optional repeated intervention procedure ("crossover") with the alternative treatment (either active cryoneurolysis or sham/placebo), again in a double-masked fashion using the same protocol as described for the initial intervention. The crossover treatment is not required for study participation, as the primary analyses will include a parallel study design for the initial intervention evaluated prior to any crossover treatment. This crossover will not affect the primary analyses, which will involve a parallel group study design and investigate the effects of cryoneurolysis within 4 months of the initial intervention.
Outcome measurements (endpoints). The primary end point will be the difference in average daily phantom pain intensity at baseline and 4 months following the initial intervention (measured with the NRS as part of the Brief Pain Inventory). The primary analyses will compare the two treatments (inter-subject comparisons) during the initial treatment period in which half of the subjects will receive active cryoneurolysis and the other half a sham/placebo treatment. Endpoints will be evaluated at baseline and post-treatment (Day 0), Days 1 and 7; and Months 1, 2, 3, 4, and 12. These same time points through Month 4 will be evaluated following the optional second (crossover) treatment.
Data collection. The questionnaires for all subjects-regardless of enrolling center-will be administered by telephone from the University of California San Diego by research coordinators specifically trained in these instruments' application, minimizing inter-rater discordance. Staff masked to treatment group assignment will perform all assessments.
- Conditions
- Post-Amputation Phantom Limb Pain
- Being tested
- Cryoneurolysis, Sham Comparator
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CryoneurolysisDevice
Also called Cryoanalgesia
Cryoneurolysis of the femoral and sciatic nerves (or their distal counterparts) in the residual limb: The cryoneurolysis device will be triggered using 3 cycles of 2-minute gas activation separated by 1-minute defrost periods. For active probes, the nitrous oxide will be deployed to the tip where a drop in temperature to -70°C will result in cryoneurolysis.
Sham ComparatorDevice
Also called placebo, control
Sham cryoneurolysis of the femoral and sciatic nerves (or their distal counterparts) in the residual limb: The cryoneurolysis device will be triggered using 3 cycles of 2-minute gas activation separated by 1-minute defrost periods. However, for sham probes, the nitrous oxide is not deployed to the tip and therefore there is no drop in temperature resulting in cryoneurolysis.
| Study group | Role | What they receive |
|---|---|---|
| Cryoneurolysis first, then optional sham crossover treatment | Active comparator | Initial treatment: Cryoneurolysis of the femoral and sciatic nerves (or their distal counterparts) in the residual limb: The cryoneurolysis device will be triggered using 3 cycles of 2-minute gas activation separated by 1-minute defrost periods. For active probes, the nitrous oxide will be deployed to the tip where a drop in temperature to -70°C will result in cryoneurolysis.
Optional sham crossover treatment: Sham cryoneurolysis of the femoral and sciatic nerves (or their distal counterparts) in the residual limb: The cryoneurolysis device will be triggered using 3 cycles of 2-minute gas activation separated by 1-minute defrost periods. However, for sham probes, the nitrous oxide is not deployed to the tip and therefore there is no drop in temperature resulting in cryoneurolysis. Receives: Device: Cryoneurolysis; Device: Sham Comparator |
| Sham Comparator first, then optional cryoneurolysis treatment | Sham comparator | Initial treatment: Sham cryoneurolysis of the femoral and sciatic nerves (or their distal counterparts) in the residual limb: The cryoneurolysis device will be triggered using 3 cycles of 2-minute gas activation separated by 1-minute defrost periods. However, for sham probes, the nitrous oxide is not deployed to the tip and therefore there is no drop in temperature resulting in cryoneurolysis.
Optional cryoneurolysis treatment: Cryoneurolysis of the femoral and sciatic nerves (or their distal counterparts) in the residual limb: The cryoneurolysis device will be triggered using 3 cycles of 2-minute gas activation separated by 1-minute defrost periods. For active probes, the nitrous oxide will be deployed to the tip where a drop in temperature to -70°C will result in cryoneurolysis. Receives: Device: Cryoneurolysis; Device: Sham Comparator |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change From Baseline in Average Daily Phantom Pain Intensity
The difference in average daily phantom pain intensity at baseline and 4 months following the initial intervention (measured with the numeric rating scale as part of the Brief Pain Inventory with a minimum value of 0 and maximum value of 10, 0=no pain and 10=worst imaginable pain)
Measured: Baseline and 4 months later (difference between the two is the primary end point)
Secondary outcomes (13)
Average Daily Phantom Pain Intensity
The average daily phantom pain intensity at between 1 day and 12 months following the initial intervention (measured with the numeric rating scale as part of the Brief Pain Inventory with a minimum value of 0 and maximum value of 10, 0=no pain and 10=worst imaginable pain)
To read the results: for the group that received cryoneurolysis initially followed by sham for the crossover treatment, "initial" Days 1 - Month 4 provide the results for those receiving cryoneurolysis while "crossover" Days 1 - Month 4 provide the results for those receiving sham treatment. This is reversed for the other treatment group that received sham initially followed by cryoneurolysis for the crossover treatment.
Measured: Endpoints will be evaluated at baseline and on Days 1 and 7; and Months 1, 2, 3, and 4 after both the initial and subsequently the crossover treatments; and 12 months after the initial treatment
Worst Daily Phantom Pain Intensity
The worst daily phantom pain intensity at between 1 day and 12 months following the initial intervention (measured with the numeric rating scale as part of the Brief Pain Inventory with a minimum value of 0 and maximum value of 10, 0=no pain and 10=worst imaginable pain). The worst pain is the maximum experienced in the previous 72 hour period (except day 1 which is the previous 24 hour period).
To read the results: for the group that received cryoneurolysis initially followed by sham for the crossover treatment, "initial" Days 1 - Month 4 provide the results for those receiving cryoneurolysis while "crossover" Days 1 - Month 4 provide the results for those receiving sham treatment. This is reversed for the other treatment group that received sham initially followed by cryoneurolysis for the crossover treatment.
Measured: Endpoints will be evaluated at baseline and on Days 1 and 7; and Months 1, 2, 3, and 4 after both the initial and subsequently the crossover treatments; and 12 months after the initial treatment
Residual Limb Pain, Average
Residual limb pain will be assessed using a Numeric Rating Scale which is a highly-sensitive measure of pain intensity with numbers ranging from 0 to 10, with zero equivalent to no pain and 10 equivalent to the worst imaginable pain.
To read the results: for the group that received cryoneurolysis initially followed by sham for the crossover treatment, "initial" Days 1 - Month 4 provide the results for those receiving cryoneurolysis while "crossover" Days 1 - Month 4 provide the results for those receiving sham treatment. This is reversed for the other treatment group that received sham initially followed by cryoneurolysis for the crossover treatment.
Measured: Endpoints will be evaluated at baseline and on Days 1 and 7; and Months 1, 2, 3, and 4 after both the initial and subsequently the crossover treatments; and 12 months after the initial treatment
Residual Limb Pain, Worst
Residual limb pain will be assessed using a Numeric Rating Scale which is a highly-sensitive measure of pain intensity with numbers ranging from 0 to 10, with zero equivalent to no pain and 10 equivalent to the worst imaginable pain. The worst pain is the maximum experienced over the previous 72 hours (24 hours for Day 1).
To read the results: for the group that received cryoneurolysis initially followed by sham for the crossover treatment, "initial" Days 1 - Month 4 provide the results for those receiving cryoneurolysis while "crossover" Days 1 - Month 4 provide the results for those receiving sham treatment. This is reversed for the other treatment group that received sham initially followed by cryoneurolysis for the crossover treatment.
Measured: Endpoints will be evaluated at baseline and on Days 1 and 7; and Months 1, 2, 3, and 4 after both the initial and subsequently the crossover treatments; and 12 months after the initial treatment
Patient Global Impression of Change
The Patient Global Impression of Change Scale is a 7-point ordinal scale requiring the subject to rate the current severity of their global situation as it relates to phantom limb pain (as defined by each individual) compared to their baseline. This scale has the words "very much worse" to the left by the number one, and "very much improved" to the right, adjacent to the number seven. The words "no change" are in the middle of the scale above the number four. The Patient Global Impression of Change Scale has been validated in over ten prospective trials, including studies specifically involving peripheral neuropathy
To read the results: for the group that received cryoneurolysis initially followed by sham for the crossover treatment, "initial" Days 1 - Month 4 provide the results for those receiving cryoneurolysis while "crossover" Days 1 - Month 4 provide the results for those receiving sham treatment. This is reversed for the other treatment group that received sham initially f
Measured: Endpoints will be evaluated on Days 1 and 7; and Months 1, 2, 3, and 4 after both the initial and subsequently the crossover treatments; and 12 months after the initial treatment
Brief Pain Inventory Interference Subscale
The Brief Pain Inventory (interference sub scale) is an instrument that measures the interference with physical and emotional functioning using a 0-10 scale (0 = no interference; 10 = complete interference). The seven interference questions involve general activity, mood, walking ability, normal work activities (both inside and outside of the home), relationships, sleep, and enjoyment of life. The seven functioning questions can be added to produce an interference subscale (0-70). A higher score reveals more interference with physical and emotional functioning.
To read the results: for the group that received cryoneurolysis initially followed by sham for the crossover treatment, "initial" Days 1 - Month 4 provide the results for those receiving cryoneurolysis while "crossover" Days 1 - Month 4 provide the results for those receiving sham treatment. This is reversed for the other treatment group that received sham initially followed by cryoneurolysis for the crossover treatment.
Measured: Endpoints will be evaluated at baseline and on Days 1 and 7; and Months 1, 2, 3, and 4 after both the initial and subsequently the crossover treatments; and 12 months after the initial treatment
Beck Depression Inventory
The Beck Depression Inventory is a 21-item instrument that measures characteristic symptoms and signs of depression, requires only a 5th grade comprehension level to adequately understand the questions, and demonstrates a high internal consistency (0.73-0.92, mean of 0.86), reliability and validity. Each of the 21 factors is rated on a 0-3 scale, and then summed to produce the total score of 0-63. Mild, moderate, and severe depression is defined with scores of 10-18, 19-29, and 30-63, respectively.
To read the results: for the group that received cryoneurolysis initially followed by sham for the crossover treatment, "initial" Month 4 provides the results for those receiving cryoneurolysis while "crossover" Month 4 provides the results for those receiving sham treatment. This is reversed for the other treatment group that received sham initially followed by cryoneurolysis for the crossover treatment.
Measured: At baseline, 4 months after the initial and crossover treatments as well as 12 months after the initial treatment
Phantom Limb Pain Frequency
Pain perceived to emanate from part of the injured limb that no longer exists. The frequency is the number of times this is experienced in the previous 72 hours.
To read the results: for the group that received cryoneurolysis initially followed by sham for the crossover treatment, "initial" Days 1 - Month 4 provide the results for those receiving cryoneurolysis while "crossover" Days 1 - Month 4 provide the results for those receiving sham treatment. This is reversed for the other treatment group that received sham initially followed by cryoneurolysis for the crossover treatment.
Measured: Endpoints will be evaluated at baseline and on Days 1 and 7; and Months 1, 2, 3, and 4 after both the initial and subsequently the crossover treatments; and 12 months after the initial treatment
Phantom Limb Pain Duration
Pain perceived to emanate from part of the injured limb that no longer exists. The duration is the average number of hours that each occurrence is experienced in the previous 72 hours.
To read the results: for the group that received cryoneurolysis initially followed by sham for the crossover treatment, "initial" Days 1 - Month 4 provide the results for those receiving cryoneurolysis while "crossover" Days 1 - Month 4 provide the results for those receiving sham treatment. This is reversed for the other treatment group that received sham initially followed by cryoneurolysis for the crossover treatment.
Measured: Endpoints will be evaluated at baseline and on Days 1 and 7; and Months 1, 2, 3, and 4 after both the initial and subsequently the crossover treatments; and 12 months after the initial treatment
Non-painful Phantom Sensations Frequency
Sensations that feel to emanate from the missing limb, but are not described as pain. The frequency is the number of times this is experienced in the previous 72 hours.
To read the results: for the group that received cryoneurolysis initially followed by sham for the crossover treatment, "initial" Days 1 - Month 4 provide the results for those receiving cryoneurolysis while "crossover" Days 1 - Month 4 provide the results for those receiving sham treatment. This is reversed for the other treatment group that received sham initially followed by cryoneurolysis for the crossover treatment.
Measured: Endpoints will be evaluated at baseline and on Days 1 and 7; and Months 1, 2, 3, and 4 after both the initial and subsequently the crossover treatments; and 12 months after the initial treatment
Non-painful Phantom Sensations Duration
Sensations that feel to emanate from the missing limb, but are not described as pain. The duration is the average duration of each experience over the previous 72 hours.
To read the results: for the group that received cryoneurolysis initially followed by sham for the crossover treatment, "initial" Days 1 - Month 4 provide the results for those receiving cryoneurolysis while "crossover" Days 1 - Month 4 provide the results for those receiving sham treatment. This is reversed for the other treatment group that received sham initially followed by cryoneurolysis for the crossover treatment.
Measured: Endpoints will be evaluated at baseline and on Days 1 and 7; and Months 1, 2, 3, and 4 after both the initial and subsequently the crossover treatments; and 12 months after the initial treatment
Residual Limb Pain Frequency
Pain that originates from a part of the injured limb that remains intact. The frequency is the number of times residual pain is experienced in the previous 72 hours.
To read the results: for the group that received cryoneurolysis initially followed by sham for the crossover treatment, "initial" Days 1 - Month 4 provide the results for those receiving cryoneurolysis while "crossover" Days 1 - Month 4 provide the results for those receiving sham treatment. This is reversed for the other treatment group that received sham initially followed by cryoneurolysis for the crossover treatment.
Measured: Endpoints will be evaluated at baseline and on Days 1 and 7; and Months 1, 2, 3, and 4 after both the initial and subsequently the crossover treatments; and 12 months after the initial treatment
Residual Limb Pain Duration
Pain that originates from a part of the injured limb that remains intact. The duration is the average number of hours that residual pain was experienced each episode in the previous 72 hours.
To read the results: for the group that received cryoneurolysis initially followed by sham for the crossover treatment, "initial" Days 1 - Month 4 provide the results for those receiving cryoneurolysis while "crossover" Days 1 - Month 4 provide the results for those receiving sham treatment. This is reversed for the other treatment group that received sham initially followed by cryoneurolysis for the crossover treatment.
Measured: Endpoints will be evaluated at baseline and on Days 1 and 7; and Months 1, 2, 3, and 4 after both the initial and subsequently the crossover treatments; and 12 months after the initial treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Feb 2018
- Study start23 Mar 2018
- Primary completion17 Aug 2021
- Study completion17 Mar 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Post-Amputation Phantom Limb PainStudies of the same condition, open and under way.
- More trials run by University of California, San DiegoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- The primary endpoint at 4 months following the initial treatment will utilize a parallel group study design; however, an optional crossover is offered to subjects following this time point.
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 144 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, San Diego
- Sponsor type
- University, hospital or other
- Collaborators
- United States Department of Defense
- Responsible party
- Principal investigator, Brian M. Ilfeld, MD, MS, University of California, San Diego
- Investigators
- Brian M Ilfeld, MD, MS, Principal investigator, University California San Diego Department of AnesthesiologyRodney Gabriel, MD, MAS, Study director, University California San Diego Department of Anesthesiology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03449667
- Sponsor's protocol ID
- CRYO for Phantom Pain (DoD)
- Other IDs
- W81XWH-17-2-0051, PR160263
- Status last verified
- Feb 2023
- First submitted
- 22 Feb 2018
- Last updated
- 17 Feb 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- Yes
- Individual data sharing
- Undecided: Pending
Publications
Moesker AA, Karl HW, Trescot AM. Treatment of phantom limb pain by cryoneurolysis of the amputated nerve. Pain Pract. 2014 Jan;14(1):52-6. doi: 10.1111/papr.12020. Epub 2012 Dec 19.
PubMed 23279331
Study at a glance
From the registry record, last updated by the sponsor on 17 Feb 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Cryoanalgesia to Treat Post-Amputation Phantom Limb Pain: A Multicenter, Randomized, Double-Masked, Placebo-Controlled, Definitive Human Subjects Clinical Trial
- ClinicalTrials.gov ID
- NCT03449667
- Acronym / sponsor ID
- CRYO for Phantom Pain (DoD)
- Conditions
- Post-Amputation Phantom Limb Pain
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 144 participants (actual)
- Lead sponsor
- University of California, San DiegoUniversity, hospital or other
- Collaborators
- United States Department of Defense
- Study start
- 23 Mar 2018 (actual)
- Primary completion
- 17 Aug 2021 (actual)
- Study completion
- 17 Mar 2022 (actual)
- First posted
- 28 Feb 2018 (actual)
- Results
- Posted 17 Feb 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 research study will include subjects with an existing lower extremity 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 target nerve(s) involved with the phantom pain. Although not required, each subject may return four 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.
Detailed description
Subjects will be asked to make no changes to their analgesic regimen for at least 1 month prior to the cryoneurolysis procedure and continuing for 4 months until the measurement of the primary end point-for the duration of the study, all patients will be allowed to continue their pre-intervention analgesics. All subjects will have a peripheral intravenous catheter inserted, standard noninvasive monitors applied, and oxygen administered via a facemask or nasal cannula. Midazolam and fentanyl (IV) will be titrated for patient comfort. The specific nerves targeted will be the sciatic and femoral (or their distal branches). The potential cryoneurolysis sites will be cleansed with chlorhexidine gluconate and isopropyl alcohol. The target nerves will be identified in a transverse cross-sectional (short axis) view using ultrasound. A Tuohy-tip needle will be inserted beneath the ultrasound transducer and directed until the needle tip is immediately adjacent to the target nerve. Local anesthetic (1-3 mL, lidocaine 2%) will be injected. This will be repeated for the femoral nerve. Within 20 minutes of the second injection, the subject's limb pain level will be evaluated on the 0-10 NRS and if higher than at baseline prior to injection, the subject will NOT continue with treatment and their participation in the study will terminate upon discharge.
Treatment group assignment (randomization). Remaining subjects will be allocated to one of two possible treatments:
- cryoneurolysis
- sham cryoneurolysis (placebo control)
Randomization will be computer-generated and stratified by enrolling institution in randomly chosen block sizes. Cryoneurolysis probes are available that either (1) pass nitrous oxide to the tip inducing freezing temperatures; or, (2) vent the nitrous oxide at the base of the probe so that no gas reaches the probe tip, resulting in no temperature change (PainBlocker, Epimed, Farmers Branch, Texas). Importantly, these probes are indistinguishable in appearance. Unmasking will not occur until statistical analysis is complete.
Intervention. The potential cryoneurolysis sites will be again cleansed with chlorhexidine gluconate and isopropyl alcohol. With the same ultrasound transducer used to previously administer local anesthetic, the target nerve will again be identified in a transverse cross-sectional (short axis) view at or distal to the deposition of local anesthetic. A cryoneurolysis device (PainBlocker, Epimed, Farmers Branch, Texas) will be inserted with the appropriate randomization-designated probe (either active or sham/placebo) and nitrous oxide. The cryoneurolysis device will be triggered using 3 cycles of 2-minute gas activation (active or sham) separated by 1-minute defrost periods. The process will be repeated with the same treatment probe for the femoral nerve (e.g., both nerves will receive either active cryoneurolysis or sham/placebo, and not a mix of the two possible treatments).
Optional crossover treatment. Four to 6 months following the initial treatment, subjects may return for an optional repeated intervention procedure ("crossover") with the alternative treatment (either active cryoneurolysis or sham/placebo), again in a double-masked fashion using the same protocol as described for the initial intervention. The crossover treatment is not required for study participation, as the primary analyses will include a parallel study design for the initial intervention evaluated prior to any crossover treatment. This crossover will not affect the primary analyses, which will involve a parallel group study design and investigate the effects of cryoneurolysis within 4 months of the initial intervention.
Outcome measurements (endpoints). The primary end point will be the difference in average daily phantom pain intensity at baseline and 4 months following the initial intervention (measured with the NRS as part of the Brief Pain Inventory). The primary analyses will compare the two treatments (inter-subject comparisons) during the initial treatment period in which half of the subjects will receive active cryoneurolysis and the other half a sham/placebo treatment. Endpoints will be evaluated at baseline and post-treatment (Day 0), Days 1 and 7; and Months 1, 2, 3, 4, and 12. These same time points through Month 4 will be evaluated following the optional second (crossover) treatment.
Data collection. The questionnaires for all subjects-regardless of enrolling center-will be administered by telephone from the University of California San Diego by research coordinators specifically trained in these instruments' application, minimizing inter-rater discordance. Staff masked to treatment group assignment will perform all assessments.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- The primary endpoint at 4 months following the initial treatment will utilize a parallel group study design; however, an optional crossover is offered to subjects following this time point.
| Arm | Type | Receives |
|---|---|---|
| Cryoneurolysis first, then optional sham crossover treatment | Active comparator | Device: Cryoneurolysis, Device: Sham ComparatorInitial treatment: Cryoneurolysis of the femoral and sciatic nerves (or their distal counterparts) in the residual limb: The cryoneurolysis device will be triggered using 3 cycles of 2-minute gas activation separated by 1-minute defrost periods. For active probes, the nitrous oxide will be deployed to the tip where a drop in temperature to -70°C will result in cryoneurolysis. Optional sham crossover treatment: Sham cryoneurolysis of the femoral and sciatic nerves (or their distal counterparts) in the residual limb: The cryoneurolysis device will be triggered using 3 cycles of 2-minute gas activation separated by 1-minute defrost periods. However, for sham probes, the nitrous oxide is not deployed to the tip and therefore there is no drop in temperature resulting in cryoneurolysis. |
| Sham Comparator first, then optional cryoneurolysis treatment | Sham comparator | Device: Cryoneurolysis, Device: Sham ComparatorInitial treatment: Sham cryoneurolysis of the femoral and sciatic nerves (or their distal counterparts) in the residual limb: The cryoneurolysis device will be triggered using 3 cycles of 2-minute gas activation separated by 1-minute defrost periods. However, for sham probes, the nitrous oxide is not deployed to the tip and therefore there is no drop in temperature resulting in cryoneurolysis. Optional cryoneurolysis treatment: Cryoneurolysis of the femoral and sciatic nerves (or their distal counterparts) in the residual limb: The cryoneurolysis device will be triggered using 3 cycles of 2-minute gas activation separated by 1-minute defrost periods. For active probes, the nitrous oxide will be deployed to the tip where a drop in temperature to -70°C will result in cryoneurolysis. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Adult patients of at least 18 years of age
- with a lower limb traumatic or surgical amputation at least 12 weeks prior to enrollment distal to the hip (femoral head remaining)
- who experience at least moderate phantom limb pain-defined as a 3 or higher on the Numeric Rating Scale (NRS; 0-10, 0= no pain; 10=worst imaginable pain)-at least daily for the previous 2 months.
- accepting of a cryoneurolysis procedure
- willing to avoid both changes to their analgesic regimen as well as elective surgical procedures from 1 month prior to and at least 4 months following the initial cryoneurolysis procedure.
Key exclusion criteria (6 listed)
- allergy to amide local anesthetics
- pregnancy
- incarceration
- inability to communicate with the investigators
- morbid obesity (body mass index > 40 kg/m2)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CryoneurolysisAlso: CryoanalgesiaCryoneurolysis of the femoral and sciatic nerves (or their distal counterparts) in the residual limb: The cryoneurolysis device will be triggered using 3 cycles of 2-minute gas activation separated by 1-minute defrost periods. For active probes, the nitrous oxide will be deployed to the tip where a drop in temperature to -70°C will result in cryoneurolysis. | Device | Cryoneurolysis first, then optional sham crossover treatment, Sham Comparator first, then optional cryoneurolysis treatment |
| Sham ComparatorAlso: placebo, controlSham cryoneurolysis of the femoral and sciatic nerves (or their distal counterparts) in the residual limb: The cryoneurolysis device will be triggered using 3 cycles of 2-minute gas activation separated by 1-minute defrost periods. However, for sham probes, the nitrous oxide is not deployed to the tip and therefore there is no drop in temperature resulting in cryoneurolysis. | Device | Cryoneurolysis first, then optional sham crossover treatment, Sham Comparator first, then optional cryoneurolysis treatment |
Primary outcome
Change From Baseline in Average Daily Phantom Pain Intensity
Time frame: Baseline and 4 months later (difference between the two is the primary end point)
The difference in average daily phantom pain intensity at baseline and 4 months following the initial intervention (measured with the numeric rating scale as part of the Brief Pain Inventory with a minimum value of 0 and maximum value of 10, 0=no pain and 10=worst imaginable pain)
13 secondary outcomes
Average Daily Phantom Pain Intensity
Time frame: Endpoints will be evaluated at baseline and on Days 1 and 7; and Months 1, 2, 3, and 4 after both the initial and subsequently the crossover treatments; and 12 months after the initial treatment
Worst Daily Phantom Pain Intensity
Time frame: Endpoints will be evaluated at baseline and on Days 1 and 7; and Months 1, 2, 3, and 4 after both the initial and subsequently the crossover treatments; and 12 months after the initial treatment
Residual Limb Pain, Average
Time frame: Endpoints will be evaluated at baseline and on Days 1 and 7; and Months 1, 2, 3, and 4 after both the initial and subsequently the crossover treatments; and 12 months after the initial treatment
Residual Limb Pain, Worst
Time frame: Endpoints will be evaluated at baseline and on Days 1 and 7; and Months 1, 2, 3, and 4 after both the initial and subsequently the crossover treatments; and 12 months after the initial treatment
Patient Global Impression of Change
Time frame: Endpoints will be evaluated on Days 1 and 7; and Months 1, 2, 3, and 4 after both the initial and subsequently the crossover treatments; and 12 months after the initial treatment
Brief Pain Inventory Interference Subscale
Time frame: Endpoints will be evaluated at baseline and on Days 1 and 7; and Months 1, 2, 3, and 4 after both the initial and subsequently the crossover treatments; and 12 months after the initial treatment
Beck Depression Inventory
Time frame: At baseline, 4 months after the initial and crossover treatments as well as 12 months after the initial treatment
Phantom Limb Pain Frequency
Time frame: Endpoints will be evaluated at baseline and on Days 1 and 7; and Months 1, 2, 3, and 4 after both the initial and subsequently the crossover treatments; and 12 months after the initial treatment
Phantom Limb Pain Duration
Time frame: Endpoints will be evaluated at baseline and on Days 1 and 7; and Months 1, 2, 3, and 4 after both the initial and subsequently the crossover treatments; and 12 months after the initial treatment
Non-painful Phantom Sensations Frequency
Time frame: Endpoints will be evaluated at baseline and on Days 1 and 7; and Months 1, 2, 3, and 4 after both the initial and subsequently the crossover treatments; and 12 months after the initial treatment
Non-painful Phantom Sensations Duration
Time frame: Endpoints will be evaluated at baseline and on Days 1 and 7; and Months 1, 2, 3, and 4 after both the initial and subsequently the crossover treatments; and 12 months after the initial treatment
Residual Limb Pain Frequency
Time frame: Endpoints will be evaluated at baseline and on Days 1 and 7; and Months 1, 2, 3, and 4 after both the initial and subsequently the crossover treatments; and 12 months after the initial treatment
Residual Limb Pain Duration
Time frame: Endpoints will be evaluated at baseline and on Days 1 and 7; and Months 1, 2, 3, and 4 after both the initial and subsequently the crossover treatments; and 12 months after the initial treatment
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Feb 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 23279331Moesker AA, Karl HW, Trescot AM. Treatment of phantom limb pain by cryoneurolysis of the amputated nerve. Pain Pract. 2014 Jan;14(1):52-6. doi: 10.1111/papr.12020. Epub 2012 Dec 19.
- Individual participant dataSharing planned: Undecided. Pending
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Brian M Ilfeld, MD, MS principal investigator
University California San Diego Department of Anesthesiology
Rodney Gabriel, MD, MAS study director
University California San Diego Department of Anesthesiology
6 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Cryoneurolysis in people with Post-Amputation Phantom Limb Pain, run by University of California, San Diego at 6 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 17 Feb 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change From Baseline in Average Daily Phantom Pain Intensity (time frame: Baseline and 4 months later (difference between the two is the primary end point)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03449667, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Feb 2023.