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

NCT ID: NCT01824082

Last Updated: 2024-05-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 144 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-12-01
• Study Completion Date: 2020-10-31

Brief 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.

Detailed 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.

Conditions

Phantom Limb Pain

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Ropivacaine 0.5%

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 assigned this treatment for their initial infusion will have the option of returning 4-16 weeks later for a second infusion of the alternate treatment: normal saline.

Group Type: EXPERIMENTAL

Perineural infusion [continuous peripheral nerve block(s)]

Intervention Type: DRUG

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.

Normal saline (salt water) infusion

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 normal saline placebo 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 assigned this treatment for their initial infusion will have the option of returning 4-16 weeks later for a second infusion of the alternate treatment: ropivacaine 0.5%.

Group Type: PLACEBO_COMPARATOR

Perineural infusion [continuous peripheral nerve block(s)]

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

United States Department of Defense

FED

Sponsor Role: collaborator

University of California, San Diego

OTHER

Sponsor Role: lead

Responsible Party

Brian M. Ilfeld, MD, MS

Professor of Anesthesiology, In Residence

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Brian M Ilfeld, MD, MS

Role: PRINCIPAL_INVESTIGATOR

University of California, San Diego

Locations

Veteran's Affairs Palo Alto Health Care System

Palo Alto, California, United States

University of California, San Diego, Hillcrest Medical Center

San Diego, California, United States

Walter Reed Army National Medical Center

Bethesda, Maryland, United States

Cleveland Clinic

Cleveland, Ohio, United States

Countries

United States

References

Ilfeld BM, Khatibi B, Maheshwari K, Madison S, Ali Sakr Esa W, Mariano ER, Kent M, Hanling S, Sessler DI, Eisenach JC, Cohen SP, Mascha E, Li S, Turan A; PAINfRE Investigators. Patient-centered results from a multicenter study of continuous peripheral nerve blocks and postamputation phantom and residual limb pain: secondary outcomes from a randomized, clinical trial. Reg Anesth Pain Med. 2023 Sep;48(9):471-477. doi: 10.1136/rapm-2023-104389. Epub 2023 Mar 9.

Reference Type: DERIVED

PMID: 36894197 (View on PubMed)

Ilfeld BM, Khatibi B, Maheshwari K, Madison SJ, Ali Sakr Esa W, Mariano ER, Kent ML, Hanling S, Sessler DI, Eisenach JC, Cohen SP, Mascha EJ, Yang D, Padwal JA, Turan A; PAINfRE Investigators. Immediate Effects of a Continuous Peripheral Nerve Block on Postamputation Phantom and Residual Limb Pain: Secondary Outcomes From a Multicenter Randomized Controlled Clinical Trial. Anesth Analg. 2021 Oct 1;133(4):1019-1027. doi: 10.1213/ANE.0000000000005673.

Reference Type: DERIVED

PMID: 34314392 (View on PubMed)

Ilfeld BM, Khatibi B, Maheshwari K, Madison SJ, Esa WAS, Mariano ER, Kent ML, Hanling S, Sessler DI, Eisenach JC, Cohen SP, Mascha EJ, Ma C, Padwal JA, Turan A; PAINfRE Investigators. Ambulatory continuous peripheral nerve blocks to treat postamputation phantom limb pain: a multicenter, randomized, quadruple-masked, placebo-controlled clinical trial. Pain. 2021 Mar 1;162(3):938-955. doi: 10.1097/j.pain.0000000000002087.

Reference Type: DERIVED

PMID: 33021563 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

Phantom Pain Treatment (DoD)

Identifier Type: -

Identifier Source: org_study_id