Trial Outcomes & Findings for Treating Phantom Limb Pain Using Continuous Peripheral Nerve Blocks: A Department of Defense Funded Multicenter Study (NCT NCT01824082)

Last Updated: 2024-05-08

Results Overview

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).

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

144 participants

Primary outcome timeframe

4 weeks following the initiation of the initial intervention.

Results posted on

2024-05-08

Participant Flow

Participant milestones

Participant milestones
Measure	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. 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.	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%. 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.
Initial Treatment STARTED	71	73
Initial Treatment COMPLETED	71	73
Initial Treatment NOT COMPLETED	0	0
Optional Crossover Treatment STARTED	40	25
Optional Crossover Treatment COMPLETED	40	25
Optional Crossover Treatment NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ropivacaine 0.5% n=71 Participants 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. 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.	Normal Saline (Salt Water) Infusion n=73 Participants 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%. 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.	Total n=144 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=71 Participants	0 Participants n=73 Participants	0 Participants n=144 Participants
Age, Categorical Between 18 and 65 years	71 Participants n=71 Participants	73 Participants n=73 Participants	144 Participants n=144 Participants
Age, Categorical >=65 years	0 Participants n=71 Participants	0 Participants n=73 Participants	0 Participants n=144 Participants
Sex: Female, Male Female	21 Participants n=71 Participants	30 Participants n=73 Participants	51 Participants n=144 Participants
Sex: Female, Male Male	50 Participants n=71 Participants	43 Participants n=73 Participants	93 Participants n=144 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Region of Enrollment United States	71 participants n=71 Participants	73 participants n=73 Participants	144 participants n=144 Participants
Body mass index	27 kg/m^2 n=71 Participants	27 kg/m^2 n=73 Participants	27 kg/m^2 n=144 Participants
Marital status Single (or divorced)	31 Participants n=71 Participants	37 Participants n=73 Participants	68 Participants n=144 Participants
Marital status Currently married	37 Participants n=71 Participants	26 Participants n=73 Participants	63 Participants n=144 Participants
Marital status Others (separated and widowed)	3 Participants n=71 Participants	10 Participants n=73 Participants	13 Participants n=144 Participants
Military Status Civilian (never in military)	56 Participants n=71 Participants	61 Participants n=73 Participants	117 Participants n=144 Participants
Military Status Veteran	14 Participants n=71 Participants	12 Participants n=73 Participants	26 Participants n=144 Participants
Military Status Active Duty	1 Participants n=71 Participants	0 Participants n=73 Participants	1 Participants n=144 Participants
Years of education	14 years n=71 Participants	13 years n=73 Participants	13 years n=144 Participants
Amputation Information Lower extremity above knee	28 Participants n=71 Participants	24 Participants n=73 Participants	52 Participants n=144 Participants
Amputation Information Lower extremity below knee	30 Participants n=71 Participants	39 Participants n=73 Participants	69 Participants n=144 Participants
Amputation Information Upper extremity above elbow	11 Participants n=71 Participants	8 Participants n=73 Participants	19 Participants n=144 Participants
Amputation Information Upper extremity below elbow	2 Participants n=71 Participants	2 Participants n=73 Participants	4 Participants n=144 Participants
Amputation Information Right (vs. left) side	32 Participants n=71 Participants	37 Participants n=73 Participants	69 Participants n=144 Participants
Amputation Information Traumatic amputation	20 Participants n=71 Participants	16 Participants n=73 Participants	36 Participants n=144 Participants
Amputation Information Surgical amputation due to cancer	5 Participants n=71 Participants	5 Participants n=73 Participants	10 Participants n=144 Participants
Amputation Information Surgical amputation due to infection	27 Participants n=71 Participants	32 Participants n=73 Participants	59 Participants n=144 Participants
Amputation Information Surgical amputation due to trauma	7 Participants n=71 Participants	6 Participants n=73 Participants	13 Participants n=144 Participants
Amputation Information Surgical amputation due to vascular deficiency	8 Participants n=71 Participants	8 Participants n=73 Participants	16 Participants n=144 Participants
Amputation Information Surgical amputation due to other cause	4 Participants n=71 Participants	6 Participants n=73 Participants	10 Participants n=144 Participants
Amputation Information History of residual limb pain	50 Participants n=71 Participants	57 Participants n=73 Participants	107 Participants n=144 Participants
Amputation Information Current residual limb pain	40 Participants n=71 Participants	48 Participants n=73 Participants	88 Participants n=144 Participants
Amputation Information Current prosthesis use	50 Participants n=71 Participants	60 Participants n=73 Participants	110 Participants n=144 Participants
Amputation Information Additional limb amputation(s)	12 Participants n=71 Participants	11 Participants n=73 Participants	23 Participants n=144 Participants
Pain immediately before and after initial local anesthetic bolus measured on the 0-10 NRS Phantom pain immediately before bolus	5 units on a scale n=71 Participants	5 units on a scale n=73 Participants	5 units on a scale n=144 Participants
Pain immediately before and after initial local anesthetic bolus measured on the 0-10 NRS Phantom pain 20 minutes after bolus	0 units on a scale n=71 Participants	0 units on a scale n=73 Participants	0 units on a scale n=144 Participants
Pain immediately before and after initial local anesthetic bolus measured on the 0-10 NRS Residual limb pain immediately before bolus	1 units on a scale n=71 Participants	3 units on a scale n=73 Participants	2 units on a scale n=144 Participants
Pain immediately before and after initial local anesthetic bolus measured on the 0-10 NRS Residual limb pain 20 minutes after bolus	0 units on a scale n=71 Participants	0 units on a scale n=73 Participants	0 units on a scale n=144 Participants
Phantom Pain previous 3 days as measured on the 0-10 NRS Current	5.0 units on a scale n=71 Participants	5.0 units on a scale n=73 Participants	5.0 units on a scale n=144 Participants
Phantom Pain previous 3 days as measured on the 0-10 NRS Least	2.0 units on a scale n=71 Participants	3.0 units on a scale n=73 Participants	2.0 units on a scale n=144 Participants
Phantom Pain previous 3 days as measured on the 0-10 NRS Average	5.0 units on a scale n=71 Participants	5.0 units on a scale n=73 Participants	5.0 units on a scale n=144 Participants
Phantom Pain previous 3 days as measured on the 0-10 NRS Worst	8.0 units on a scale n=71 Participants	8.0 units on a scale n=73 Participants	8.0 units on a scale n=144 Participants
Residual limb pain previous 3 days ( Numeric Rating Scale) Current	1.0 units on a scale n=71 Participants	3.0 units on a scale n=73 Participants	2.0 units on a scale n=144 Participants
Residual limb pain previous 3 days ( Numeric Rating Scale) Least	0 units on a scale n=71 Participants	2 units on a scale n=73 Participants	1 units on a scale n=144 Participants
Residual limb pain previous 3 days ( Numeric Rating Scale) Average	3 units on a scale n=71 Participants	4.0 units on a scale n=73 Participants	3 units on a scale n=144 Participants
Residual limb pain previous 3 days ( Numeric Rating Scale) Worst	5 units on a scale n=71 Participants	6.0 units on a scale n=73 Participants	5 units on a scale n=144 Participants
Phantom pain relief from medication (%) 0-25%	26 Participants n=71 Participants	22 Participants n=73 Participants	48 Participants n=144 Participants
Phantom pain relief from medication (%) 26-50%	21 Participants n=71 Participants	18 Participants n=73 Participants	39 Participants n=144 Participants
Phantom pain relief from medication (%) 51-75%	5 Participants n=71 Participants	13 Participants n=73 Participants	18 Participants n=144 Participants
Phantom pain relief from medication (%) 76-100%	8 Participants n=71 Participants	4 Participants n=73 Participants	12 Participants n=144 Participants
Phantom pain relief from medication (%) Did not use any medication or pain treatment	11 Participants n=71 Participants	16 Participants n=73 Participants	27 Participants n=144 Participants
Residual pain relief from medication (%) 0-25%	23 Participants n=71 Participants	19 Participants n=73 Participants	42 Participants n=144 Participants
Residual pain relief from medication (%) 26-50%	10 Participants n=71 Participants	16 Participants n=73 Participants	26 Participants n=144 Participants
Residual pain relief from medication (%) 51-75%	5 Participants n=71 Participants	9 Participants n=73 Participants	14 Participants n=144 Participants
Residual pain relief from medication (%) 76-100%	8 Participants n=71 Participants	3 Participants n=73 Participants	11 Participants n=144 Participants
Residual pain relief from medication (%) Did not use any medication or pain treatment	25 Participants n=71 Participants	26 Participants n=73 Participants	51 Participants n=144 Participants
Pain Interference components ( Brief Pain Inventory) General activity	6.0 units on a scale n=71 Participants	5.0 units on a scale n=73 Participants	5 units on a scale n=144 Participants
Pain Interference components ( Brief Pain Inventory) Mood	6.0 units on a scale n=71 Participants	6.0 units on a scale n=73 Participants	6 units on a scale n=144 Participants
Pain Interference components ( Brief Pain Inventory) Walking ability	5.0 units on a scale n=71 Participants	5.0 units on a scale n=73 Participants	5 units on a scale n=144 Participants
Pain Interference components ( Brief Pain Inventory) Normal work	6.0 units on a scale n=71 Participants	5.0 units on a scale n=73 Participants	5 units on a scale n=144 Participants
Pain Interference components ( Brief Pain Inventory) Relations with other people	4.0 units on a scale n=71 Participants	4.0 units on a scale n=73 Participants	4 units on a scale n=144 Participants
Pain Interference components ( Brief Pain Inventory) Sleep	8.0 units on a scale n=71 Participants	7.0 units on a scale n=73 Participants	7 units on a scale n=144 Participants
Pain Interference components ( Brief Pain Inventory) Enjoyment of life	6.0 units on a scale n=71 Participants	6.0 units on a scale n=73 Participants	6 units on a scale n=144 Participants
Depression as measured with the Beck's Depression Inventory	15 units on a scale n=71 Participants	14 units on a scale n=73 Participants	14 units on a scale n=144 Participants
Beck Depression Inventory Minimal depression	25 Participants n=71 Participants	30 Participants n=73 Participants	55 Participants n=144 Participants
Beck Depression Inventory Mild depression	16 Participants n=71 Participants	14 Participants n=73 Participants	30 Participants n=144 Participants
Beck Depression Inventory Moderate depression	24 Participants n=71 Participants	20 Participants n=73 Participants	44 Participants n=144 Participants
Beck Depression Inventory Severe depression	6 Participants n=71 Participants	9 Participants n=73 Participants	15 Participants n=144 Participants

PRIMARY outcome

Timeframe: 4 weeks following the initiation of the initial intervention.

Population: "Average Phantom Limb Pain Intensity" at 4 weeks following the initiation of the first intervention before participants had the option to crossover to the other intervention

Outcome measures

Outcome measures
Measure	Ropivacaine 0.5% n=71 Participants 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. 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.	Normal Saline (Salt Water) Infusion n=73 Participants 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%. 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.	Ropivacaine 0.5% Followed by Placebo 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 ropivacaine 0.5% 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). Subjects assigned this treatment returned 4-16 weeks later for a second infusion of the alternate treatment: normal saline.	Placebo Followed by Ropivacaine 0.5% 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 in this group returned returned 4-16 weeks later for a second infusion of the alternate treatment: ropivacaine 0.5%.
"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)	3.0 score on a scale Standard Deviation 2.9	4.5 score on a scale Standard Deviation 2.6	—	—

SECONDARY outcome

Timeframe: 4 weeks following the initiation of the initial intervention

Population: Perception of well-being(as measured with the Patient Global Impression of Change Scale) at 4 weeks following the initiation of the first intervention before participants had the option to crossover to the other intervention.

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).

Outcome measures

Outcome measures
Measure	Ropivacaine 0.5% n=71 Participants 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. 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.	Normal Saline (Salt Water) Infusion n=73 Participants 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%. 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.	Ropivacaine 0.5% Followed by Placebo 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 ropivacaine 0.5% 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). Subjects assigned this treatment returned 4-16 weeks later for a second infusion of the alternate treatment: normal saline.	Placebo Followed by Ropivacaine 0.5% 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 in this group returned returned 4-16 weeks later for a second infusion of the alternate treatment: ropivacaine 0.5%.
Perception of Well-being (as Measured With the Patient Global Impression of Change Scale).	5.0 score on a scale Interval 4.0 to 7.0	4.0 score on a scale Interval 4.0 to 5.0	—	—

SECONDARY outcome

Timeframe: 4 weeks following initiation of the initial intervention

Population: Physical and emotional functioning ( as measured with the Brief Pain Inventory Interference Domain) at 4 weeks following the initiation of the first intervention before participants had the option to crossover to the other intervention.

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).

Outcome measures

Outcome measures
Measure	Ropivacaine 0.5% n=71 Participants 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. 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.	Normal Saline (Salt Water) Infusion n=73 Participants 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%. 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.	Ropivacaine 0.5% Followed by Placebo 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 ropivacaine 0.5% 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). Subjects assigned this treatment returned 4-16 weeks later for a second infusion of the alternate treatment: normal saline.	Placebo Followed by Ropivacaine 0.5% 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 in this group returned returned 4-16 weeks later for a second infusion of the alternate treatment: ropivacaine 0.5%.
Physical and Emotional Functioning 4 Weeks Following Initiation of Intervention (as Measured With the Brief Pain Inventory Interference Domain). Total of 7 components	11 score on a scale Interval 0.0 to 38.0	28 score on a scale Interval 4.0 to 45.0	—	—
Physical and Emotional Functioning 4 Weeks Following Initiation of Intervention (as Measured With the Brief Pain Inventory Interference Domain). General activity	1.0 score on a scale Interval 0.0 to 6.0	5.0 score on a scale Interval 0.0 to 7.0	—	—
Physical and Emotional Functioning 4 Weeks Following Initiation of Intervention (as Measured With the Brief Pain Inventory Interference Domain). Mood	0 score on a scale Interval 0.0 to 6.0	5.0 score on a scale Interval 0.0 to 8.0	—	—
Physical and Emotional Functioning 4 Weeks Following Initiation of Intervention (as Measured With the Brief Pain Inventory Interference Domain). Walking ability	0 score on a scale Interval 0.0 to 3.0	3.0 score on a scale Interval 0.0 to 7.0	—	—
Physical and Emotional Functioning 4 Weeks Following Initiation of Intervention (as Measured With the Brief Pain Inventory Interference Domain). Normal Work	0 score on a scale Interval 0.0 to 6.0	3.0 score on a scale Interval 0.0 to 6.0	—	—
Physical and Emotional Functioning 4 Weeks Following Initiation of Intervention (as Measured With the Brief Pain Inventory Interference Domain). Relations with others	0 score on a scale Interval 0.0 to 5.0	2.5 score on a scale Interval 0.0 to 6.5	—	—
Physical and Emotional Functioning 4 Weeks Following Initiation of Intervention (as Measured With the Brief Pain Inventory Interference Domain). Sleep	2.5 score on a scale Interval 0.0 to 8.0	5.5 score on a scale Interval 0.0 to 8.0	—	—
Physical and Emotional Functioning 4 Weeks Following Initiation of Intervention (as Measured With the Brief Pain Inventory Interference Domain). Enjoyment of life	1.0 score on a scale Interval 0.0 to 7.0	4.0 score on a scale Interval 0.0 to 7.0	—	—

SECONDARY outcome

Timeframe: 4 weeks following initiation of the initial intervention

Population: Depression(as measured with the Beck Depression Inventory) at 4 weeks following the initiation of the first intervention before participants had the option to crossover to the other intervention.

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.

Outcome measures

Outcome measures
Measure	Ropivacaine 0.5% n=71 Participants 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. 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.	Normal Saline (Salt Water) Infusion n=73 Participants 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%. 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.	Ropivacaine 0.5% Followed by Placebo 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 ropivacaine 0.5% 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). Subjects assigned this treatment returned 4-16 weeks later for a second infusion of the alternate treatment: normal saline.	Placebo Followed by Ropivacaine 0.5% 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 in this group returned returned 4-16 weeks later for a second infusion of the alternate treatment: ropivacaine 0.5%.
Depression 4 Weeks Following Initiation of Intervention (as Measured With the Beck Depression Inventory).	6 score on a scale Interval 2.0 to 17.0	13 score on a scale Interval 4.0 to 22.0	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 and 12 months following initiation of the initial intervention

Population: All subjects received the initial intervention. However, only a subset of each group chose to participate in the optional crossover treatment that occurred 1-4 months following the initiation of the initial treatment infusion. For those who did participate in the optional crossover treatment, they received the alternative treatment as their initial treatment (e.g., subjects who initially received placebo saline subsequently received Ropivacaine 0.5%, and vice versa).

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.

Outcome measures

Outcome measures
Measure	Ropivacaine 0.5% n=46 Participants 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. 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.	Normal Saline (Salt Water) Infusion n=33 Participants 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%. 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.	Ropivacaine 0.5% Followed by Placebo Infusion n=25 Participants 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 ropivacaine 0.5% 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). Subjects assigned this treatment returned 4-16 weeks later for a second infusion of the alternate treatment: normal saline.	Placebo Followed by Ropivacaine 0.5% Infusion n=40 Participants 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 in this group returned returned 4-16 weeks later for a second infusion of the alternate treatment: ropivacaine 0.5%.
Change in Physical and Emotional Functioning at 6 and 12 Months Compared With Baseline (as Measured With the Brief Pain Inventory Interference Domain). Sleep (12 months following initiation of intervention)	-1.0 score on a scale Interval -6.0 to 0.0	0 score on a scale Interval -6.0 to 0.0	-1.0 score on a scale Interval -2.0 to 0.0	-0.5 score on a scale Interval -6.5 to 0.5
Change in Physical and Emotional Functioning at 6 and 12 Months Compared With Baseline (as Measured With the Brief Pain Inventory Interference Domain). Enjoyment of life (12 months following initiation of intervention)	-1.0 score on a scale Interval -5.0 to 0.0	-1.0 score on a scale Interval -6.0 to 1.0	0 score on a scale Interval -5.0 to 0.0	0 score on a scale Interval -3.5 to 1.0
Change in Physical and Emotional Functioning at 6 and 12 Months Compared With Baseline (as Measured With the Brief Pain Inventory Interference Domain). General activity (6months following initiation of intervention)	-1.5 score on a scale Interval -6.0 to 0.0	-2.0 score on a scale Interval -5.0 to 1.0	0 score on a scale Interval -1.5 to 1.0	-2.0 score on a scale Interval -5.0 to 0.0
Change in Physical and Emotional Functioning at 6 and 12 Months Compared With Baseline (as Measured With the Brief Pain Inventory Interference Domain). Mood (6months following initiation of intervention)	-1.0 score on a scale Interval -5.0 to 0.0	-1.0 score on a scale Interval -4.0 to 0.0	0 score on a scale Interval -2.0 to 1.0	-1.0 score on a scale Interval -5.0 to 0.0
Change in Physical and Emotional Functioning at 6 and 12 Months Compared With Baseline (as Measured With the Brief Pain Inventory Interference Domain). Walking ability (6months following initiation of intervention)	0 score on a scale Interval -7.0 to 0.0	-1.0 score on a scale Interval -5.0 to 0.0	0 score on a scale Interval -1.0 to 0.0	-1.0 score on a scale Interval -3.0 to 0.0
Change in Physical and Emotional Functioning at 6 and 12 Months Compared With Baseline (as Measured With the Brief Pain Inventory Interference Domain). Normal work (6months following initiation of intervention)	-2.5 score on a scale Interval -6.5 to 0.0	-1.0 score on a scale Interval -5.0 to 0.0	0 score on a scale Interval -1.5 to 1.0	-1.0 score on a scale Interval -6.0 to 0.0
Change in Physical and Emotional Functioning at 6 and 12 Months Compared With Baseline (as Measured With the Brief Pain Inventory Interference Domain). Relations with others (6months following initiation of intervention)	-1.0 score on a scale Interval -5.5 to 0.0	0 score on a scale Interval -5.0 to 0.0	0 score on a scale Interval -1.5 to 1.0	0 score on a scale Interval -3.0 to 1.0
Change in Physical and Emotional Functioning at 6 and 12 Months Compared With Baseline (as Measured With the Brief Pain Inventory Interference Domain). Sleep (6months following initiation of intervention)	-3.8 score on a scale Interval -7.0 to 0.0	-1.5 score on a scale Interval -6.0 to 0.0	0 score on a scale Interval -1.0 to 0.0	0 score on a scale Interval -6.0 to 0.0
Change in Physical and Emotional Functioning at 6 and 12 Months Compared With Baseline (as Measured With the Brief Pain Inventory Interference Domain). Enjoyment of life (6months following initiation of intervention)	-2.0 score on a scale Interval -7.5 to 0.0	-1.0 score on a scale Interval -5.0 to 0.0	0 score on a scale Interval -2.0 to 0.0	-2.0 score on a scale Interval -5.0 to 0.0
Change in Physical and Emotional Functioning at 6 and 12 Months Compared With Baseline (as Measured With the Brief Pain Inventory Interference Domain). General activity (12 months following initiation of intervention)	-1.0 score on a scale Interval -4.0 to 0.0	-1.0 score on a scale Interval -5.0 to 0.0	-1.0 score on a scale Interval -4.0 to 1.0	-1.0 score on a scale Interval -3.5 to 0.0
Change in Physical and Emotional Functioning at 6 and 12 Months Compared With Baseline (as Measured With the Brief Pain Inventory Interference Domain). Mood (12 months following initiation of intervention)	0 score on a scale Interval -4.0 to 0.0	-1.0 score on a scale Interval -4.0 to 0.0	-1.0 score on a scale Interval -4.0 to 0.0	-0.5 score on a scale Interval -3.8 to 1.0
Change in Physical and Emotional Functioning at 6 and 12 Months Compared With Baseline (as Measured With the Brief Pain Inventory Interference Domain). Walking ability (12 months following initiation of intervention)	-1.0 score on a scale Interval -6.0 to 0.0	0 score on a scale Interval -5.0 to 0.0	0 score on a scale Interval -3.0 to 0.0	0 score on a scale Interval -4.5 to 0.0
Change in Physical and Emotional Functioning at 6 and 12 Months Compared With Baseline (as Measured With the Brief Pain Inventory Interference Domain). Normal work (12 months following initiation of intervention)	-1.0 score on a scale Interval -5.0 to 0.0	-1.0 score on a scale Interval -5.0 to 0.0	-3.0 score on a scale Interval -6.0 to 0.0	-1.5 score on a scale Interval -5.3 to 0.0
Change in Physical and Emotional Functioning at 6 and 12 Months Compared With Baseline (as Measured With the Brief Pain Inventory Interference Domain). Relations with others (12 months following initiation of intervention)	-1.0 score on a scale Interval -2.0 to 0.0	0 score on a scale Interval -3.0 to 0.0	-1.0 score on a scale Interval -4.0 to 0.0	-0.5 score on a scale Interval -4.0 to 1.0

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 and 12 months following initiation of the initial intervention

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.

Outcome measures

Outcome measures
Measure	Ropivacaine 0.5% n=46 Participants 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. 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.	Normal Saline (Salt Water) Infusion n=33 Participants 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%. 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.	Ropivacaine 0.5% Followed by Placebo Infusion n=25 Participants 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 ropivacaine 0.5% 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). Subjects assigned this treatment returned 4-16 weeks later for a second infusion of the alternate treatment: normal saline.	Placebo Followed by Ropivacaine 0.5% Infusion n=40 Participants 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 in this group returned returned 4-16 weeks later for a second infusion of the alternate treatment: ropivacaine 0.5%.
Change in Depression 6 and 12 Months Compared With Baseline (as Measured With the Beck Depression Inventory). Month 6	-3.0 units on a scale Interval -11.0 to 0.0	-2.0 units on a scale Interval -6.0 to 0.0	-1.5 units on a scale Interval -2.0 to 0.0	-4.0 units on a scale Interval -8.0 to 0.0
Change in Depression 6 and 12 Months Compared With Baseline (as Measured With the Beck Depression Inventory). Month 12	-4.0 units on a scale Interval -12.0 to -1.0	-2.0 units on a scale Interval -9.0 to 0.0	-1.5 units on a scale Interval -3.0 to 0.0	-4.0 units on a scale Interval -9.0 to -1.0

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 and 12 months following initiation of intervention

Outcome measures

Outcome measures
Measure	Ropivacaine 0.5% n=46 Participants 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. 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.	Normal Saline (Salt Water) Infusion n=33 Participants 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%. 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.	Ropivacaine 0.5% Followed by Placebo Infusion n=25 Participants 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 ropivacaine 0.5% 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). Subjects assigned this treatment returned 4-16 weeks later for a second infusion of the alternate treatment: normal saline.	Placebo Followed by Ropivacaine 0.5% Infusion n=40 Participants 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 in this group returned returned 4-16 weeks later for a second infusion of the alternate treatment: ropivacaine 0.5%.
Perception of Well-being (as Measured With the Patient Global Impression of Change Scale). 6 months following initiation of intervention	7.0 units on a scale Interval 4.0 to 7.0	5.0 units on a scale Interval 4.0 to 7.0	4.0 units on a scale Interval 4.0 to 5.0	4.0 units on a scale Interval 4.0 to 7.0
Perception of Well-being (as Measured With the Patient Global Impression of Change Scale). 12 months following initiation of intervention	6.0 units on a scale Interval 4.0 to 7.0	5.0 units on a scale Interval 4.0 to 7.0	4.0 units on a scale Interval 4.0 to 7.0	4.0 units on a scale Interval 4.0 to 7.0

OTHER_PRE_SPECIFIED outcome

Timeframe: 4 weeks following the initial intervention

Population: Data analysed 28 days following the initial intervention and before the crossover treatment. So its analysed based on participants included in each arm group for the initial treatment. Not applicable for crossover treatment option.

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

Outcome measures

Outcome measures
Measure	Ropivacaine 0.5% n=71 Participants 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. 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.	Normal Saline (Salt Water) Infusion n=73 Participants 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%. 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.	Ropivacaine 0.5% Followed by Placebo 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 ropivacaine 0.5% 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). Subjects assigned this treatment returned 4-16 weeks later for a second infusion of the alternate treatment: normal saline.	Placebo Followed by Ropivacaine 0.5% 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 in this group returned returned 4-16 weeks later for a second infusion of the alternate treatment: ropivacaine 0.5%.
Masking Assessment Definitely Active	10 Participants	2 Participants	—	—
Masking Assessment Probably Active	17 Participants	8 Participants	—	—
Masking Assessment Does not know	18 Participants	18 Participants	—	—
Masking Assessment Probably Saline	16 Participants	33 Participants	—	—
Masking Assessment Definitely Saline	3 Participants	4 Participants	—	—
Masking Assessment Missing	7 Participants	8 Participants	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Days 1, 7, 14, 21

Population: Days 1, 7, 14, 21 following the initiation of the first intervention.

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