Cryoanalgesia to Treat Post-Amputation Phantom Limb Pain: A Department of Defense Funded Multicenter Study

Study Overview
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Brief Summary
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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
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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.

Official Title
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Cryoanalgesia to Treat Post-Amputation Phantom Limb Pain: A Multicenter, Randomized, Double-Masked, Placebo-Controlled, Definitive Human Subjects Clinical Trial

Conditions
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Post-Amputation Phantom Limb Pain

Intervention / Treatment
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* Device: Cryoneurolysis
* Device: Sham Comparator


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cryoneurolysis first, then optional sham crossover treatment<br>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. | Device: Cryoneurolysis<br>* 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.<br>* Other names: Cryoanalgesia;Device: Sham Comparator<br>* 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.<br>* Other names: placebo, control;|
| Sham Comparator: Sham Comparator first, then optional cryoneurolysis treatment<br>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. | Device: Cryoneurolysis<br>* 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.<br>* Other names: Cryoanalgesia;Device: Sham Comparator<br>* 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.<br>* Other names: placebo, control;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | Baseline and 4 months later (difference between the two is the primary end point) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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 | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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 |