Treating Phantom Limb Pain Using Continuous Peripheral Nerve Blocks: A Department of Defense Funded Multicenter Study

Phantom Limb Pain Clinical Trial

— DoD-PLP-Tx  

Official title:

Treating Intractable Post-Amputation Phantom Limb Pain With Ambulatory Continuous Peripheral Nerve Blocks

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01824082
• Other study ID #: Phantom Pain Treatment (DoD)
• Status: Completed
• Phase: Phase 4
• Start date: December 1, 2013
• Est. completion date: October 2020

Study information

• Verified date: May 2024
• Source: University of California, San Diego
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

When a limb is traumatically severed, pain perceived in the part of the body that no longer exists often develops. This is called "phantom limb" pain, and is different from "stump" pain, which is pain within the part of the limb that remains intact. Unfortunately, phantom pain resolves in only 16% of people, with the rest experiencing this pain for the remainder of the lives. There is currently no reliable treatment for phantom limb pain.

The exact reason that phantom limb pain occurs is unclear, but when a nerve is cut-as happens with a traumatic amputation-changes occur in the brain and spinal cord that actually worsen with increasing phantom pain. These abnormal changes may often be corrected by putting local anesthetic-termed a "peripheral nerve block"-on the injured nerve, keeping any "bad signals" from reaching the brain, with resolution of the phantom limb pain. However, when the nerve block ends after a few hours, the phantom pain returns. But, this demonstrates that the brain abnormalities-and phantom pain-that occur with an amputation may be dependent upon the "bad" signals being sent from the injured nerve(s), suggesting that a very long peripheral nerve block-lasting many days rather than hours-may permanently reverse the abnormal changes in the brain, and provide lasting relief from phantom pain.

Until recently, extending a peripheral nerve block beyond 16 hours was unrealistic. However, a treatment option called a "continuous peripheral nerve block" is now available. This technique involves the placement of a tiny tube-smaller than a piece of spaghetti-through the skin and next to the nerves supplying the amputated limb. The tiny tube may be placed with minimal discomfort in about 15 minutes. Numbing medicine called local anesthetic is then infused through the tube, blocking any signals that the injured nerve sends to the spinal cord and brain. Using a small, portable infusion pump, this prolonged nerve block may be provided in individuals' own homes.

The ultimate objective of the proposed research study is to determine if a 6-day continuous peripheral nerve block provided at home is an effective treatment for persistent phantom limb pain following a traumatic limb amputation. The primary hypothesis (what the researchers predict) is that phantom limb pain intensity will be significantly decreased 4 weeks following treatment with a 6-day continuous peripheral nerve block.

Description:

Background. The combination of increased munitions force, use of improvised explosive devices, and casualty survival rates has resulted in a dramatic increase in the percentage of injured combat veterans living with a traumatic amputation. Of American Veteran amputees, 35-98% develop chronic, intractable pain perceived as being from the missing limb, a phenomenon termed "phantom limb pain." This pain resolves in only 16% of afflicted individuals, and there is currently no reliable treatment. The etiology of phantom pain remains unclear, but evidence suggests that severing a nerve provokes changes in the spinal cord, thalamus, and cerebral cortex. When neural input from an amputated limb is blocked with local anesthetic (a peripheral nerve block), cortical abnormalities and phantom pain frequently resolve. However, when the single-injection nerve block resolves after a few hours, the phantom pain returns. These findings demonstrate that cortical abnormalities and phantom pain may be maintained from abnormal peripheral input, suggesting that a peripheral nerve block of extended duration-lasting many days rather than hours-may permanently reorganize cortical pain mapping, thus providing lasting relief from phantom pain. A "continuous peripheral nerve block" (CPNB) involves the percutaneous insertion of a catheter directly adjacent to the peripheral nerves supplying an affected limb. Local anesthetic infused via the catheter(s) induces a completely insensate extremity for as long as desired without any systemic side effects. Additionally, CPNB may be provided on an ambulatory basis using a small, portable pump to infuse the local anesthetic.

Objective. To determine if ambulatory CPNB is an effective treatment for intractable phantom limb pain following a traumatic limb amputation. Previously-published small, uncontrolled series describe patients immediately following surgical amputation whose phantom limb pain dramatically decreased or completely resolved with CPNB. We have data from a randomized, double-masked, placebo-controlled, crossover pilot study suggesting great promise treating intractable phantom limb pain with ambulatory CPNB: participants (n=3) experienced no change in their phantom pain following a 6-day infusion of normal saline; however, with a 6-day CPNB of potent local anesthetic administered 4 months later, subjects (n=2; one patient returned to duty before crossover infusion) experienced complete resolution of their phantom limb pain. Within the 12-week follow-up period, one subject experienced no phantom pain recurrence; and the other subject reported mild pain occurring once each week of just a small fraction of his original pain.

Specific Aims. The primary hypothesis is that phantom limb pain intensity will be significantly decreased 4 weeks following an ambulatory CPNB (as measured by the Numeric Rating Scale of the Brief Pain Inventory).

Study Design. We propose a multicenter, randomized, double-masked, placebo-controlled, simultaneous parallel and crossover, human-subjects clinical trial. We will include subjects with an existing upper or lower amputation who experience phantom limb pain at least daily for the previous 4 weeks. Catheter site(s) will be determined by amputation location. Subjects will be randomized to receive one of two study solutions in a double-masked manner: either a local anesthetic (ropivacaine 0.5%) or placebo (normal saline). Catheters will be removed after 6 days of at-home infusion. Although not required, each subject has the option to return for the alternative treatment four weeks later (crossover infusion). The primary endpoint will be the difference in average phantom pain intensity at baseline and 4 weeks following the initial infusion as measured with the Numeric Rating Scale between treatment groups for the initial infusion. Major secondary endpoints will involve intra- and inter-subject comparisons of additional measures of pain and health-related quality-of-life.

Clinical Impact. From 2001-2006, over 70% of all U.S. military casualties endured a major limb injury, with an amputation rate of 28% within Operation Enduring Freedom alone. Previous conflicts have left tens-of-thousands of United States Armed Forces Veterans with missing limbs. CPNB are now relatively ubiquitous within the United States, but applied nearly exclusively to provide acute post-injury/surgical analgesia. If the proposed study demonstrates that ambulatory CPNB is a reliable treatment for intractable phantom limb pain, the resulting impact in treating the consequences of traumatic amputation will be immediate and profound, as healthcare providers within the United States Armed Forces and Veterans Affairs Medical Centers already have expertise placing and managing perineural catheters. Currently, CPNB is provided exclusively in the acute setting-to treat pain immediately following a battlefield injury or surgery-and not chronic, intractable phantom limb pain. However, because there is little technical difference in providing CPNB for acute versus chronic pain, the thousands of U.S. Veterans and active duty personnel suffering from intractable phantom pain could be treated relatively easily, rapidly, and with negligible additional costs.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 144
• Est. completion date: October 2020
• Est. primary completion date: November 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 18 years of age or older

• Upper or lower limb traumatic or surgical amputation at least 12 weeks prior to enrollment at or distal to the mid-humerus or hip (femoral head remaining), respectively; and including at least one metacarpal or metatarsal bone, respectively.

• Experiencing at least moderate phantom limb pain (defined as 2 or higher on the numeric rating scale, NRS 0-10), at least three times each week for the previous 8 weeks.

• Accepting of an ambulatory continuous peripheral nerve block for 6 days.

• Willing to avoid changes to their analgesic regimen from 4 weeks prior to and at least 4 weeks following the initial catheter placement (preferably 4 weeks following the second/crossover catheter insertion as well).

• Having a "caretaker" who will transport the subject home following the catheter insertion(s), and remain with the subject for the first night of the infusions.

Exclusion Criteria:

• Known renal insufficiency

• Allergy to study medications

• Pregnancy

• Incarceration

• Inability to communicate with the investigators

• Morbid obesity (BMI greater than 40)

• Comorbidity that results in moderate-to-severe functional limitation (ASA greater than 2)

• Possessing any contraindication to ambulatory perineural catheter placement or perineural local anesthetic infusion:

• Current infection

• Immune-compromised status of any etiology

• Uncontrolled anxiety/panic disorder

• Inability to contact investigators during the perineural infusion

Related Conditions & MeSH terms

• Phantom Limb
• Phantom Limb Pain

Intervention

Drug:
• Perineural infusion [continuous peripheral nerve block(s)]
Electronic, programmable, portable infusion pumps will be used to administer perineural study solution at fixed rates for over 6 days. Subjects will receive a total of 1,100 mL of study fluid from either one (upper extremity) or two (lower extremity) pump and external reservoir combinations. The continuous basal infusion rate will be determined by catheter location: femoral 2.5 mL/h; popliteal-sciatic 5 mL/h; and infraclavicular 7.5 mL/h (37.5 mg/h for both upper and lower extremity subjects). No patient-controlled bolus dose will be included. Subjects will have the option of returning 4-16 weeks later for a second infusion of the alternate treatment solution.

Locations

Country	Name	City	State
United States	Walter Reed Army National Medical Center	Bethesda	Maryland
United States	Cleveland Clinic	Cleveland	Ohio
United States	Veteran's Affairs Palo Alto Health Care System	Palo Alto	California
United States	University of California, San Diego, Hillcrest Medical Center	San Diego	California

Sponsors (2)

Lead Sponsor	Collaborator
University of California, San Diego	United States Department of Defense

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in Physical and Emotional Functioning at 6 and 12 Months Compared With Baseline (as Measured With the Brief Pain Inventory Interference Domain).	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). The use of both single items (e.g., mood) and the composite scores is supported. The reported data is the reported interference sub scale at 6 and 12 months compared with baseline.	6 and 12 months following initiation of the initial intervention
Other	Change in Depression 6 and 12 Months Compared With Baseline (as Measured With the 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. The data presented are the Beck Depression Inventory at 6 and 12 months compared with baseline.	6 and 12 months following initiation of the initial intervention
Other	Perception of Well-being (as Measured With the Patient Global Impression of Change Scale).	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.	6 and 12 months following initiation of intervention
Other	Masking Assessment	Subjects were asked which study fluid they believed they were receiving during the initial infusion: The possible responses were: ?Definitely active ?Probably active ?Does not know ? Probably saline ? Definitely saline	4 weeks following the initial intervention
Other	"Average" Phantom Limb Pain	The "average" phantom limb pain experienced over the previous 3 days evaluated with the 0-10 Numeric Rating Scale with 0=no pain and 10=worst imaginable pain	Days 1, 7, 14, 21
Other	"Worst" Phantom Limb Pain	The worst phantom limb pain experienced over the previous 3 days evaluated with the 0-10 Numeric Rating Scale with 0=no pain and 10=worst imaginable pain	Days 1, 7, 14, 21, 28
Other	"Least" Phantom Limb Pain	The least phantom limb pain experienced over the previous 3 days evaluated with the 0-10 Numeric Rating Scale with 0=no pain and 10=worst imaginable pain	Days 1, 7, 14, 21, 28.
Other	"Current" Phantom Limb Pain	The current phantom limb pain at the time of the data collection phone call evaluated with the 0-10 Numeric Rating Scale with 0=no pain and 10=worst imaginable pain	Days 1, 7, 14, 21, 28.
Other	"Average" Residual Limb Pain	The "average" residual limb pain experienced over the previous 3 days evaluated with the 0-10 Numeric Rating Scale with 0=no pain and 10=worst imaginable pain	Days 1, 7, 14, 21, 28
Other	"Worst" Residual Limb Pain	The worst residual limb pain experienced over the previous 3 days evaluated with the 0-10 Numeric Rating Scale with 0=no pain and 10=worst imaginable pain	Days 1, 7, 14, 21, 28.
Other	"Least" Residual Limb Pain	The least residual limb pain experienced over the previous 3 days evaluated with the 0-10 Numeric Rating Scale with 0=no pain and 10=worst imaginable pain	Days 1, 7, 14, 21, 28
Other	"Current" Residual Limb Pain	The current residual limb pain at the time of the data collection phone call evaluated with the 0-10 Numeric Rating Scale with 0=no pain and 10=worst imaginable pain	Days 1, 7, 14, 21, 28.
Other	Change in "Average" Phantom Limb Pain at 6 and 12 Months From the Baseline Measurement (as Measured With the 0-10 Numeric Rating Scale)	The "average" phantom limb pain experienced over the previous 3 days evaluated with the 0-10 Numeric Rating Scale with 0=no pain and 10=worst imaginable pain. The data presented is the change in the "average" phantom limb pain at 6 and 12 months from the baseline measurement.	6 and 12 months following baseline (the day of the initiation of the initial intervention)
Other	Change in "Worst" Phantom Limb Pain at 6 and 12 Months From the Baseline Measurement (as Measured With the 0-10 Numeric Rating Scale)	The "worst" phantom limb pain experienced over the previous 3 days evaluated with the 0-10 Numeric Rating Scale with 0=no pain and 10=worst imaginable pain. The data presented is the change in the "worst" phantom limb pain at 6 and 12 months from the baseline measurement.	6 and 12 months following baseline (the day of the initiation of the initial intervention)
Other	Change in "Average" Residual Limb Pain at 6 and 12 Months From the Baseline Measurement (as Measured With the 0-10 Numeric Rating Scale)	The "average" residual limb pain experienced over the previous 3 days evaluated with the 0-10 Numeric Rating Scale with 0=no pain and 10=worst imaginable pain. The data presented is the change in the "average" residual limb pain at 6 and 12 months from the baseline measurement.	6 and 12 months following baseline (the day of the initiation of the initial intervention)
Other	Change in "Worst" Residual Limb Pain at 6 and 12 Months From the Baseline Measurement (as Measured With the 0-10 Numeric Rating Scale)	The "worst" residual limb pain experienced over the previous 3 days evaluated with the 0-10 Numeric Rating Scale with 0=no pain and 10=worst imaginable pain. The data presented is the change in the "worst" residual limb pain at 6 and 12 months from the baseline measurement.	6 and 12 months following baseline (the day of the initiation of the initial intervention)
Primary	"Average" Phantom Limb Pain Intensity 4 Weeks Following Initiation of an Ambulatory Continuous Peripheral Nerve Block (as Measured by the Numeric Rating Scale Within the Brief Pain Inventory)	Phantom pain will be assessed using a Numeric Rating Scale (NRS) as part of the Brief Pain Inventory (short form), with the "average" pain score designated as the primary endpoint. In addition, average and worst residual limb pain NRS will be recorded separately from the phantom pain scores. The NRS 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. These data are 4 weeks after the initiation of the FIRST intervention (and not the optional crossover treatment).	4 weeks following the initiation of the initial intervention.
Secondary	Perception of Well-being (as Measured With the Patient Global Impression of Change Scale).	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. These data are from 4 weeks after the initiation of the FIRST intervention (and not the optional crossover treatment).	4 weeks following the initiation of the initial intervention
Secondary	Physical and Emotional Functioning 4 Weeks Following Initiation of Intervention (as Measured With the Brief Pain Inventory Interference Domain).	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). The use of both single items (e.g., mood) and the composite scores is supported. These data are from 4 weeks after the initiation of the FIRST intervention (and not the optional crossover treatment).	4 weeks following initiation of the initial intervention
Secondary	Depression 4 Weeks Following Initiation of Intervention (as Measured With the 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. This data is 4 weeks following the initiation of the initial intervention, and NOT the optional crossover treatment.	4 weeks following initiation of the initial intervention