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Prophylactic Regenerative Peripheral Nerve Interfaces to Prevent Postamputation Pain

Kubiak, Carrie A. M.D.; Kemp, Stephen W. P. Ph.D.; Cederna, Paul S. M.D.; Kung, Theodore A. M.D.

Plastic and Reconstructive Surgery: September 2019 - Volume 144 - Issue 3 - p 421e-430e
doi: 10.1097/PRS.0000000000005922
Hand/Peripheral Nerve: Original Articles
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Background: Postamputation pain affects a large number of individuals living with major limb loss. Regenerative peripheral nerve interfaces are constructs composed of a transected peripheral nerve implanted into an autologous free muscle graft. The authors have previously shown that regenerative peripheral nerve interfaces can be used to treat symptomatic end neuromas that develop after major limb amputation. In this study, they investigated the potential of prophylactic interfaces to prevent the formation of symptomatic neuromas and mitigate phantom limb pain.

Methods: Patients who underwent limb amputation with and without prophylactic regenerative peripheral nerve interface implantation were identified. A retrospective review was performed to ascertain patient demographics, level of amputation, and postoperative complications. Documentation of symptomatic neuromas and phantom limb pain was noted.

Results: Postoperative outcomes were evaluated in a total of 90 patients. Forty-five patients underwent interface implantation at the time of primary amputation, and 45 control patients underwent amputation without interfaces. Six control patients (13.3 percent) developed symptomatic neuromas in the postoperative period compared with zero (0.0 percent) in the prophylactic interface group (p = 0.026). Twenty-three interface patients (51.1 percent) reported phantom limb pain, compared with 41 control patients (91.1 percent; p < 0.0001).

Conclusions: Prophylactic regenerative peripheral nerve interfaces in major limb amputees resulted in a lower incidence of both symptomatic neuromas and phantom limb pain compared with control patients undergoing amputation without regenerative peripheral nerve interfaces, suggesting that prevention of peripheral neuromas following amputation may diminish the central pain mechanisms that lead to phantom limb pain.

CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Ann Arbor, Mich.

From the Department of Surgery, Section of Plastic and Reconstructive Surgery, and the Department of Biomedical Engineering, University of Michigan.

Received for publication June 16, 2018; accepted February 13, 2019.

Presented at the 63rd Annual Meeting of the Plastic Surgery Research Council, in Birmingham, Alabama, May 17 through 20, 2018.

Disclosure:The authors have no financial interest to declare in relation to the content of this article.

Theodore A. Kung, M.D., Section of Plastic Surgery, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, Mich. 48109-5456, thekung@med.umich.edu

An estimated 185,000 limb amputations are performed in the United States annually,1 and a total of 3.6 million people are projected to be living with major limb loss by the year 2050.2 Amputation of a major limb often results in painful and disabling sensory experiences.3 Unfortunately, for many of these individuals, this pain results in the inability to wear a prosthesis4 and an overall decreased quality of life.5

Postamputation pain can be categorized into two distinct categories: phantom limb pain and residual limb pain. Phantom limb pain is characterized by painful sensations perceived in the missing limb after amputation and has been reported to occur in as many as 85 percent of amputees.3,6,7 The exact cause of phantom limb pain has been debated for many decades and is likely a combination of central nervous system changes, peripheral conditions, and psychological factors.8,9 Residual limb pain is experienced in the remaining portion of the limb after amputation. Residual limb pain is frequently attributed to postsurgical causes such as bone spurs, infection or, more commonly, neuromas. Neuromas are an inevitable sequela of major nerve injury or transection, and clinically symptomatic neuromas may occur in 12 to 50 percent of major limb amputations.10,11 Symptomatic neuromas present as discrete areas of exquisite tenderness which, on being palpated, are associated with shooting pain and dysesthesia in the distribution of the involved peripheral nerve.

The regenerative peripheral nerve interface was developed in our laboratory as a surgically fabricated construct composed of a transected peripheral nerve implanted into an autogenous free muscle graft12–14 (Fig. 1). The regenerative peripheral nerve interface was originally designed as a means of harnessing residual peripheral nerve signals for intuitive control of a prosthetic limb. However, animal studies revealed a notable absence of neuroma formation within the regenerative peripheral nerve interface, and that discovery supported the potential use of regenerative peripheral nerve interfaces for the treatment of symptomatic neuromas in human patients.12 The use of regenerative peripheral nerve interfaces to prophylactically prevent symptomatic neuromas has not yet been investigated; therefore, the purpose of the present study was to determine the efficacy of regenerative peripheral nerve interfaces to reduce the incidence of postamputation neuroma and to decrease the overall postamputation pain experience. We hypothesize that prophylactic regenerative peripheral nerve interfaces at the time of primary amputation would result in lower rates of both symptomatic neuromas and phantom limb pain compared with traditional amputation techniques.

Fig. 1.

Fig. 1.

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PATIENTS AND METHODS

Study Design

This study was approved by the University of Michigan Institutional Review Board. To determine the number of subjects required in each group, a power analysis was conducted based on pilot data.12 Assuming a desired α = 0.05 and β = 0.20, the study will be sufficiently powered using a total of 20 patients in each subgroup. This sample size will provide 80 percent power to detect a greater than 53 percent difference between groups on independent t tests.

Patients were identified through a registry of individuals who underwent primary major limb amputation with prophylactic regenerative peripheral nerve interface implantation between August of 2013 and August of 2017. “Primary” amputation was defined as the first amputation of a given limb, in contrast to “secondary” or “revision” amputation. Control patients were then selected from a registry of 178 amputees who underwent primary major limb amputation without regenerative peripheral nerve interface surgery during the same study period. Postamputation pain experiences differ between the sexes15 and those with upper versus lower limb amputations.16 As such, control patients were matched to the regenerative peripheral nerve interface population by sex and level of amputation. Patients with at least 4 weeks of follow-up were included in the study.17,18 To ensure reliable self-expression of pain,19 only subjects aged 8 years or older were included.

A retrospective chart review was performed for each patient based on a comprehensive evaluation of records from all providers who cared for the patient after surgery. Postoperative progress notes and clinic notes written by members of the surgical and physical medicine and rehabilitation service teams were specifically scrutinized. Special attention was directed toward patient demographics, level of amputation, indication for amputation, surgeon specialty, postoperative complications, and pain outcomes. Because of the retrospective nature of the study and the fact that validated pain scales were not consistently used, pain outcomes were described as “present” or “not present.” Patients were identified as having a symptomatic neuroma if medical records included documentation of physical findings consistent with neuroma (i.e., strongly positive Tinel sign) and a diagnosis in the provider assessment. Patients were identified as having phantom limb pain if medical documentation revealed patient report of “painful” phantom limb experience at any point in their postoperative course. Nonpainful phantom phenomena (i.e., phantom sensations) were considered distinct from phantom limb pain and not included as a pain outcome measure.

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Surgical Technique

Patients underwent limb amputation using standard techniques according each surgeon’s preference and experience. In prophylactic regenerative peripheral nerve interface patients, the major peripheral nerves were isolated and sharply transected before the regenerative peripheral nerve interface procedure. In control patients, major peripheral nerves were managed with either traction neurectomy, suture ligature, burial within a nearby muscle, or a combination of these techniques.

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Regenerative Peripheral Nerve Interface Creation

All major transected peripheral nerves were prioritized for regenerative peripheral nerve interface creation at the time of primary amputation (Figs. 1 and 2). For example, in transtibial amputations, the tibial, deep peroneal, and superficial peroneal nerves were usually dissected out for regenerative peripheral nerve interface creation. Some surgeons also elected to pursue additional regenerative peripheral nerve interface creation on cutaneous sensory nerves (e.g., sural and saphenous) at their own discretion. Each regenerative peripheral nerve interface construct was derived from free (nonvascularized) autologous muscle grafts harvested from healthy muscle of the amputated limb. Each muscle graft measured approximately 30 × 15 × 5 mm and was harvested along the axis of muscle fibers to limit trauma to the muscle fibers within the free graft. The end of the transected nerve was placed within the muscle belly of the free muscle graft in an orientation that was parallel to the muscle fibers. Parallel orientation was preferred to optimize successful axonal reinnervation of regenerated muscle fibers. Next, the nerve was secured distally with 6-0 nonabsorbable monofilament sutures in an epimysial-to-epineurial fashion. The muscle graft was then wrapped completely around the nerve and epimysial securing sutures were placed (Figs. 1 and 2). Blunt dissection was performed within the residual limb to provide a space for each regenerative peripheral nerve interface in an area remote from the surgical incision and from the weight-bearing surface of the limb.

Fig. 2.

Fig. 2.

In more proximal amputations, intraneural dissection was performed to separate the nerve into two or more fascicles, and subsequently each fascicle was used to create a separate regenerative peripheral nerve interface. For example, in a transfemoral amputation, fascicular dissection of the sciatic nerve allows for implantation of a total of three prophylactic regenerative peripheral nerve interfaces on the tibial, deep peroneal, and superficial peroneal nerve fascicles. Separating large nerves into fascicles theoretically improves axon-to-muscle graft volume ratio to promote reinnervation and therefore reduce neuroma formation.12

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Postoperative Course

All patients were admitted for postoperative monitoring and then discharged either to home or to a rehabilitation center. Follow-up consisted of inpatient and/or outpatient evaluation by both the primary surgical service and the physical medicine and rehabilitation service, who monitored patients for postoperative complications and pain control.

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Statistical Analysis

Descriptive statistics were used to quantitatively describe the characteristics of study and control patients. Continuous variables were summarized using means and standard deviations, whereas categorical variables were summarized as percentages. The relationship between patient characteristics, operative time, and mean duration of follow-up was compared between patient groups by independent samples t tests or univariate analysis of variance as appropriate. Fisher’s exact test was used to compare categorical data between cohorts. Significance was set at α < 0.05.

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RESULTS

Demographics

A total of 90 patients were included in this study. Forty-five patients underwent regenerative peripheral nerve interface implantation at the time of primary limb amputation and 45 control patients underwent standard amputation without regenerative peripheral nerve interfaces. Table 1 summarizes patient demographic and clinical data for both patient cohorts. Patient groups were matched for age, sex, level of amputation, and mean duration of follow-up. In both cohorts, the majority of subjects were male [n = 33 (73.3 percent) versus n = 32 (71.1 percent)]. The mean age in the prophylactic regenerative peripheral nerve interface group was 46.0 ± 17.4 years (range, 12 to 79 years), compared with 44.2 ± 13.8 years (range, 13 to 76 years) in the control group (p = 0.5880). Comparison of relevant comorbidities revealed that there were significantly more patients with peripheral vascular disease in the control group (Table 1). Mean duration of follow-up was 357.2 ± 265.6 days (range, 29 to 897 days) in the regenerative peripheral nerve interface group versus 358.3 ± 320.0 days in the control group (range, 30 to 1035 days; p = 0.986).

Table 1. - Patient Characteristics
Prophylactic RPNI Group (%) Control Group (%)
No. of patients 45 45
Age, yr
 Mean ± SD 46.0 ± 17.4 44.2 ± 13.8
 Range 12–79 13–76
Male 33 (73.3) 32 (71.1)
BMI, kg/m2
 Mean ± SD 28.7 ± 8.0 29.6 ± 7.0
 Range 17.0–54.9 17.4–48.0
Tobacco history 21 (46.7) 31 (68.9)
Diabetes 14 (31.1) 21 (46.7)
PVOD 7 (15.6) 20 (44.4)
Heart disease 7 (15.6) 14 (31.1)
Liver disease 1 (2.2) 2 (4.4)
COPD 3 (6.7) 5 (11.1)
R
PNI, regenerative peripheral nerve interface; BMI, body mass index; PVOD, pulmonary venoocclusive disease; COPD, chronic obstructive pulmonary disease.

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Operative Details

Table 2 presents procedural details for both patient groups. In the regenerative peripheral nerve interface cohort, a total of 47 operations were performed to complete 52 major limb amputations. In the control group, 50 operations were performed to complete 52 amputations. Operative time was significantly longer in the regenerative peripheral nerve interface group than in the control group (p < 0.0001).

Table 2. - Operative Details
Prophylactic RPNI Group (%) Control Group (%)
Total no. of operations 47 50
No. of surgeons 14 25
Total no. of limb amputations 52 52
Transtibial (BKA) 37 (82.2) 38 (84.4)
Transfemoral (AKA) 9 (20) 10 (22.2)
Transradial (BEA) 3 (6.7) 2 (4.4)
Transhumeral (AEA) 2 (4.4) 1 (2.2)
Glenohumeral 1 (2.2) 1 (2.2)
Average operative time ± SD, min 152 ± 68 90 ± 38
R
PNI, regenerative peripheral nerve interface; BKA, below-knee amputation; AKA, above-knee amputation; BEA, below-elbow amputation; AEA, above-elbow amputation.

Figure 3 displays the amputation surgeon specialty in the prophylactic regenerative peripheral nerve interface and control patient groups. The vast majority of prophylactic regenerative peripheral nerve interface amputations were performed by plastic surgeons [n = 42 (80.8 percent)], whereas vascular surgeons performed the majority of amputations in the control group [n = 25 (48.1 percent)]. Figure 4 compares the indications for amputation between patient cohorts. In both patient groups, the three most common indications for amputation were trauma, osteomyelitis from chronic wounds, and limb ischemia (Fig. 5).

Fig. 3.

Fig. 3.

Fig. 4.

Fig. 4.

Fig. 5.

Fig. 5.

In the prophylactic regenerative peripheral nerve interface patient group, a total of 159 regenerative peripheral nerve interfaces were placed on transected peripheral nerves at the time of primary amputation (Table 3). Most commonly, regenerative peripheral nerve interfaces were created using the tibial nerve (n = 45), the deep peroneal nerve (n = 35), and the superficial peroneal nerve (n = 35). Table 4 displays methods to address the transected peripheral nerve in the control patient cohort. The most common technique used in the control group was suture ligature [n = 17 (32.7 percent)], followed by a combination of techniques (traction neurectomy, buried in muscle, and/or suture ligature) [n = 10 (19.2 percent)].

Table 3. - Nerves Used in Prophylactic Regenerative Peripheral Nerve Interface Creation
Characteristic No.
Lower extremity
 Sciatic 7
 Femoral 1
 Tibial 45
 Common peroneal 4
 Deep peroneal 35
 Superficial peroneal 35
 Saphenous 5
 Sural 4
 Total no. of lower extremity RPNIs 136
Upper extremity
 Median cord 2
 Lateral cord 2
 Posterior cord 2
 Musculocutaneous 2
 Ulnar 5
 Median 5
 Radial 2
 Radial sensory 2
 Intercostal brachial cutaneous 1
 Total no. of upper extremity RPNIs 23
 Total no. of prophylactic RPNIs 159
R
PNIs, regenerative peripheral nerve interfaces.

Table 4. - Nerve Management in Control Patients
Management No. (%)
Traction neurectomy 9 (17.3)
Suture ligature 17 (32.7)
Buried in muscle 2 (3.9)
Simple transection 1 (1.9)
Combination of techniques 10 (19.2)
Unknown, not described in operative report 13 (25.0)

Postoperatively, regenerative peripheral nerve interface patients were admitted to the hospital for an average of 11.7 ± 21.1 days (range, 1 to 108 days) before discharge, compared with control patients, who were admitted an average of 17.6 ± 24.3 days (range, 2 to 136 days; p = 0.2220) before discharge. Most patients in both groups were discharged to an inpatient rehabilitation program (regenerative peripheral nerve interface patients, n = 24; and control patients, n = 26).

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Complications

Table 5 summarizes postoperative patient outcomes. Total complications were higher in the control group (55.6 percent versus 31.1 percent; p = 0.0328). Delayed wound healing complications occurred at lower rates in the prophylactic regenerative peripheral nerve interface patient group than in the control group (26.7 percent versus 53.3 percent; p = 0.0174). Major complications were defined as events that resulted in unplanned readmission or operation. A total of three patients in the prophylactic regenerative peripheral nerve interface group (6.7 percent) and 12 patients in the control group (26.7 percent) experienced a major complication resulting in an unplanned operative procedure. The most common reason for reoperation was postoperative residual limb infection requiring formal drainage and washout.

Table 5. - Postoperative Complications
Complication Prophylactic RPNI (%) Control (%)
Minor*
 Delayed wound healing 12 (26.7) 24 (53.3)
 Surgical-site infection 6 (13.3) 12 (26.7)
 Hematoma 0 (0) 1 (2.2)
Major*
 Readmission for complication 0 (0) 3 (6.7)
 Postoperative infection, OR washout 1 (2.2) 6 (13.3)
 Wound dehiscence from fall, OR closure 1 (2.2) 0 (0)
 Delayed wound healing, OR débridement 1 (2.2) 3 (6.7)
Any 14 (31.1) 25 (55.6)
R
PNI, regenerative peripheral nerve interface; OR, operating room.
*
Percentage of amputations.
Percentage of patients.

Three prophylactic regenerative peripheral nerve interface patients died before the end of the study period from causes unrelated to the prophylactic regenerative peripheral nerve interface surgery itself. One patient died 270 days after his regenerative peripheral nerve interface surgery because of complications from widespread metastatic lung cancer. An immunosuppressed renal transplant patient died 404 days after her regenerative peripheral nerve interface surgery secondary to myocardial infarction. A third patient with multiple medical comorbidities including diabetes, heart failure, end-stage renal disease, peripheral arterial disease, and deep vein thrombosis on anticoagulation died at home from an unknown cause 49 days after her amputation and regenerative peripheral nerve interface surgery. In the control group, two patients died before the end of the study period. One patient died 120 days after his amputation because of complications from heart failure. The second died 336 days after surgery from unknown causes.

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Pain Outcomes

Table 6 summarizes postamputation pain outcomes. Six control patients (13.3 percent) developed symptomatic neuromas in the residual limb during the study period. The vast majority of patients in the control group also described phantom limb pain at some point in their postoperative course [n = 41 (91.1 percent)]. Conversely, zero of the regenerative peripheral nerve interface patients developed symptomatic neuromas at any point during the study period. Furthermore, of the 45 patients with 52 major limbs amputated, only 23 (51.1 percent) developed any documented phantom pain during the postoperative course.

Table 6. - Postamputation Pain Outcomes in Prophylactic Regenerative Peripheral Nerve Interface and Control Patient Groups
Prophylactic RPNI (%) Control (%) p
Symptomatic neuroma 0 (0) 6 (13.3) 0.026*
Phantom limb pain 23 (51.1) 41 (91.1) <0.0001*
Mean duration of follow up ± SD, days 357.1 ± 265.6 358.3 ± 320.8 0.986
R
PNI, regenerative peripheral nerve interface
*
Statistically significant. Incidence of symptomatic neuroma and phantom limb pain were both significantly less in the prophylactic RPNI patient cohort.

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DISCUSSION

Symptomatic neuroma is an extremely common sequela of major limb amputation20 yet remains an extremely challenging condition to treat. Neuroma formation occurs when axonal injury results in inflammation and aberrant axonal sprouting that forms exquisitely painful bulbs of disorganized regenerative nerve tissue.21 At present, there remains no gold standard for treatment of neuromas; numerous different therapeutic modalities have been explored without reliable success.22 The refractory nature of postamputation pain underscores the need for pain prevention. To achieve this goal, prophylactic strategies aimed at reducing the incidence of postamputation pain must be implemented at the time of primary amputation.

Traction neurectomy remains the most commonly used method for addressing major peripheral nerves during amputation.23 In this technique, the peripheral nerve is placed under firm traction before it is sharply transected, and this allows for proximal retraction of the cut nerve end. It is important to note that this method does not seek to prevent neuroma formation; it simply hopes to place the expected neuroma in a less symptomatic location. Unfortunately, traction neurectomy is only inconsistently effective when used in isolation.24,25

In 1986, Dellon and Mackinnon reported a series of 78 neuromas in 60 patients treated by neuroma resection and implantation of the proximal nerve into adjacent muscle.26 Of the 78 nerves, eight required reoperation for insufficient relief of pain. With an average follow-up of 31 months, “excellent” pain relief was obtained in 42 percent of patients and “little to no” pain relief was obtained in 19 percent. Histopathology of treatment failures were found to have “nonclassic neuroma” formation.27,28 Although the random, disorganized whirling of myelinated nerve fibers as seen in “classic neuromas” was not observed, the implanted, transected nerve was found to have no interaction with the muscle fibers in which it was implanted (i.e., no neuromuscular junctions), and contained small regenerating clusters of immature nerve fibers.26

Additional methods described to prevent neuroma recurrence include nerve transposition techniques,23,29,30 silicone capping,31 proximal nerve crush,32 and coaptation procedures.33,34 However, these approaches have also been associated with incomplete relief of pain23 or symptomatic neuroma recurrence.34 For example, a recent retrospective study by Domeshek et al. investigated patient-reported outcomes following surgical treatment for neuroma pain.32 A total of 70 patients were treated for neuroma using the proximal nerve crush technique with neuroma excision and proximal transposition. Initial postoperative patient-reported outcomes demonstrated significant improvement compared with preoperative patient-reported outcomes.32 However, of the 17 patients with long-term follow-up of at least 2 years, three (17.6 percent) required subsequent procedures because of insufficient relief of pain, and three (17.6 percent) said they would not undergo the operation if they had to again.32 In theory, the proximal nerve crush functions to move the nerve regeneration front away from the end of the nerve, reducing the number of axons that reach the distal stump and the formation of symptomatic neuroma. However, performing a proximal crush induces a second injury in the same nerve, increasing the possibility of a double-crush phenomenon and a neuroma-in-continuity proximally, and may lead to increased pain from central feedback.

Our results indicate that use of prophylactic regenerative peripheral nerve interfaces is an extremely effective technique for the prevention of postamputation neuroma formation. Similar to the targeted muscle reinnervation technique,35 the regenerative peripheral nerve interface provides distal physiologic targets (i.e., healthy, acutely denervated muscle fibers) for regenerating axons to make new neuromuscular junctions.13 Muscle fibers within the regenerative peripheral nerve interface construct are both nonvascularized and denervated. The muscle graft undergoes a process of regeneration and revascularization while axonal sprouting of the implanted nerve occurs. The number of axons without a functional connection are greatly reduced, resulting in the prevention of erratic axonal sprouting responsible for neuroma formation. Histologic rodent and primate animal studies confirm the formation of new neuromuscular junctions and the absence of neuromas in regenerative peripheral nerve interfaces.13 It can be noted that targeted muscle reinnervation differs from the regenerative peripheral nerve interface in its potential to also reinnervate intramuscular sensory organelles such as Golgi tendon organ and stretch receptors. However, unlike targeted muscle reinnervation, the surgical creation of regenerative peripheral nerve interfaces is a rather simple surgical technique that does not require microsurgical expertise.

Our data also indicate a significantly lower incidence of phantom pain (51.1 percent) in the prophylactic regenerative peripheral nerve interface patient cohort, compared with both our control cohort (91.1 percent; p < 0.0001) and published rates in the literature (12 to 50 percent).6,7,10,11,36 This important finding may help to further elucidate the complex mechanisms responsible for generating phantom limb pain, a phenomenon that is mediated by the central nervous system. The exact pathophysiologic mechanisms behind phantom limb pain remain incompletely understood; however, a multifactorial cause is likely. The high correlation between residual limb pain and phantom limb pain provides compelling evidence that central nerve system pain is exacerbated by peripheral nervous system pain.37 It is postulated that high-intensity, peripheral noxious input may sensitize central neural structures involved in pain perception.9,38–40 Overactive, injured peripheral nerves cause central sensitization by making nerves hyperexcitable. Conversely, central nervous system sensitization can be prevented by the interruption of noxious afferent input through treatment of the peripheral nerve problem.39 For example, studies have found that injection of local anesthetic into a painful residual limb can result in the temporary relief of phantom pain.37,41 In further support of peripheral nerve contribution of phantom limb pain, a series of retrospective and prospective studies have reported that peripheral nerve interventions could lead to improvement in both residual limb pain23 and phantom limb pain.39

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Limitations

This study is limited by issues relating to its retrospective study design, such as reliance on medical records and the potential for selection bias. Rates of symptomatic neuromas in either study group may have been underreported at follow-up visits. Unlike phantom limb pain, which is a widely known term in the amputee population, the concept of neuroma pain may be more esoteric and therefore patients may not as readily or accurately report neuroma pain. Furthermore, clinicians may not have consistently tested for the presence of symptomatic neuromas at every follow-up visit. Because of the retrospective nature of this study, we were also limited in the ability to collect detailed information about each individual’s pain experiences. Specifics about pain onset, duration, character, severity, frequency, medication use, and quality-of-life measures were not consistently documented in the medical chart and thus not collected for analysis in this study. The recall period was similarly infrequently reported. However, these pain outcome measures will be collected in future prospective studies. It should be noted that pain experiences may vary greatly between individuals, and patient-reported pain outcomes can be very difficult to quantify and interpret. In this way, our binary pain outcome design actually helps protect against pain outcome misinterpretation.

Although patient cohorts were very similar with regard to age, body mass index, level of amputation, and length of follow-up, they were significantly different with respect to baseline comorbidities. For example, the proportion of patients with peripheral vascular disease was significantly higher in the control patient population compared with the prophylactic regenerative peripheral nerve interface patients. These differences may contribute to the observed differences in postoperative complication rates and postoperative length of hospital stay between the two patient groups. The discrepancy in baseline comorbidities may also explain the relatively lower incidence of neuromas in the control group (13.3 percent) compared with previously published rates. For example, patients with longstanding diabetes may be less likely to detect neuroma given their baseline nerve dysfunction, and patients with heart disease may be less likely to ambulate regularly using a prosthesis and therefore may not be as hindered by symptomatic neuromas. Ideally, patient groups would be matched perfectly in all domains, including age, sex, level of amputation, baseline comorbidity status, and length of postoperative stay. However, the retrospective nature of the study did not allow the prophylactic regenerative peripheral nerve interface and control groups to be matched with regard to baseline comorbidity status and length of postoperative stay.

Lastly, it should be noted that prophylactic regenerative peripheral nerve interface and control cohorts were not matched for indication or mechanism of amputation. The literature on risk factors for the development of phantom limb pain is voluminous and contradictory. For example, a 2012 study by Nikolajsen reported preamputation extremity pain increased the risk of phantom pain following amputation42; however, a more recent investigation found no association between preamputation and phantom limb pain.43 Other studies have also concluded that the cause of amputation is unrelated to the rate of phantom limb pain. Because of the contradictory nature of the literature, we did not match for cause or mechanism of amputation. However, this will be considered in future prospective investigations.

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CONCLUSIONS

The high prevalence and refractory nature of both symptomatic neuromas and phantom limb pain emphasize the need for strategies that effectively prevent postamputation pain. This study demonstrates that prophylactic implantation of regenerative peripheral nerve interfaces is associated with the reduced formation of symptomatic neuromas and the development of debilitating phantom limb pain. Future research is required to define, quantify, and characterize the role of the regenerative peripheral nerve interface in postamputation pain prevention and treatment. Findings from this study support the execution of a prospective study to investigate the efficacy of using regenerative peripheral nerve interfaces to prevent both neuroma pain and phantom limb pain, and to elucidate the relationship between these two forms of postamputation pain.

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