Long-Term Treatment of Chronic Postamputation Pain With Bioelectric Nerve Block: Twelve-Month Results of the Randomized, Double-Blinded, Cross-Over QUEST Study.

OBJECTIVE: The multicenter, randomized, double-blinded, active-sham controlled trial (high-freQUEncy nerve block for poST amputation pain [QUEST]) was conducted to show the safety and efficacy of a novel, peripherally placed high-frequency nerve block (HFNB) system in treating chronic postamputation pain (PAP) in patients with lower limb amputations. The primary outcomes from QUEST were reported previously. This study presents the long-term, single-cross-over, secondary outcomes of on-demand HFNB treatment for chronic PAP. MATERIALS AND METHODS: After the three-month randomized period, subjects in the active-sham group were crossed over to receive therapy for 12 months. Subjects self-administered HFNB therapy as needed and reported their pain (numerical rating scale [NRS]; range, 1-10) before and 30 and 120 minutes after each treatment. Pain medication use was reported throughout the study. Pain-days per week and quality of life (QOL) were assessed using the Brief Pain Inventory (BPI). Adverse events (AEs) were recorded for all subjects implanted for 12 months. RESULTS: Of 180 subjects implanted in QUEST, 164 (91%) were included in the cross-over period, and 146 (82%) completed follow-up. By month 12, average NRS pain in the combined cohort was reduced by 2.3 ± 2.2 points (95% CI, 1.7-2.8; p < 0.0001) 30 minutes after treatment and 2.9 ± 2.4 points (95% CI, 2.2-3.6; p < 0.0001) 120 minutes after treatment. Mean pain-days per week were significantly reduced (-3.5 ± 2.7 days; p < 0.001), and subject daily opioid use was reduced by 6.7 ± 29.0 morphine equivalent dose from baseline to month 12 (p = 0.013). Mean BPI-interference scores (QOL) improved by 2.7 ± 2.7 points from baseline (p < 0.001). The incidence of nonserious AEs and serious AEs was 72% (130/180) and 42% (76/180), respectively; serious device-related AEs occurred in 15 of 180 subjects (8%). CONCLUSION: Overall, HFNB delivered directly to the damaged peripheral nerve provided sustained, on-demand relief of acute PAP exacerbations, reduced opioid utilization, and improved QOL for patients with lower limb amputations with chronic PAP.

Ultrasound appearance of regenerative peripheral nerve interface with clinical correlation.

OBJECTIVE: To describe the ultrasound (US) appearance of regenerative peripheral nerve interfaces (RPNIs) in humans, and correlate clinically and with histologic findings from rat RPNI. MATERIALS AND METHODS: Patients (≥ 18 years) who had undergone RPNI surgery within our institution between the dates of 3/2018 and 9/2019 were reviewed. A total of 21 patients (15 male, 6 female, age 21-82 years) with technically adequate US studies of RPNIs were reviewed. Clinical notes were reviewed for the presence of persistent pain after RPNI surgery. Histologic specimens of RPNIs in a rat model from prior studies were compared with the US findings noted in this study. RESULTS: There was a variable appearance to the RPNIs including focal changes involving the distal nerve, nerve-muscle graft junction, and area of the distal sutures. The muscle grafts varied in thickness with accompanying variable echogenic changes. No interval change was noted on follow-up US studies. Diffuse hypoechoic swelling with loss of the fascicular structure of the nerve within the RPNI and focal hypoechoic changes at the nerve-muscle graft junction were associated with clinical outcomes. US findings corresponded to histologic findings in the rat RPNI. CONCLUSION: Ultrasound imaging can demonstrate various morphologic changes involving the nerve, muscle, and interface between these two biological components of RPNIs. These changes correspond to expected degenerative and regenerative processes following nerve resection and muscle reinnervation and should not be misconstrued as pathologic in all cases. N5 and N1 morphologic type changes of the RPNI were found to be associated with symptoms.

The Canine Postamputation Pain (CAMPPAIN) initiative: a retrospective study and development of a diagnostic scale.

OBJECTIVE: To develop a scale to diagnose and assess the severity of postamputation pain (PAP) in dogs. STUDY DESIGN: Single-center retrospective study. ANIMALS: A total of 66 dogs that underwent thoracic or pelvic limb amputation and 139 dogs that underwent tibial plateau leveling osteotomy (TPLO) at a veterinary teaching hospital. METHODS: An online survey regarding postoperative behavioral changes was sent to owners. Categorical, multiple-choice responses were entered into a univariable logistic regression model and tested for association with amputation using the Wald test. If p < 0.2, variables were forwarded to a multivariable logistic regression model for manual build. Model simplicity and predictive ability were optimized using the area under the receiver operating curve (AUROC) characteristic, and model calibration was assessed using the Hosmer-Lemeshow test. The selected model was converted to an integer scale (0-10), the Canine Postamputation Pain (CAMPPAIN) scale. Univariable logistic regression related each dog's calculated score to the probability of PAP. RESULTS: Multivariable logistic regression identified four independent predictors of PAP (p < 0.05): 1) restlessness or difficulty sleeping, 2) episodes of panic or anxiety, 3) sudden vocalization, and 4) compulsive grooming of the residual limb. Score AUROC was 0.70 (95% confidence interval = 0.63-0.78) with good calibration (Hosmer-Lemeshow statistic p = 0.82). A score of 2 corresponded to a risk probability of 0.5. Taking a score ≥ 2 to indicate PAP, score specificity and sensitivity were 92.1% and 36.4%, respectively. When this score was used to diagnose PAP, prevalence was 36.4% (24/66) and 7.9% (11/139) in the amputation and TPLO groups, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Postamputation pain is characterized by specific postoperative behaviors and appears to affect approximately one-third of canine amputees. The CAMPPAIN scale generated from these data could facilitate diagnosis, treatment and further study of PAP but requires external validation.

Targeted Muscle Reinnervation in the Hand: Treatment and Prevention of Pain After Ray Amputation.

Targeted muscle reinnervation (TMR), originally developed as an experimental technique for prosthetic control, has been shown to be safe and effective for the treatment and prevention of postamputation pain. Targeted muscle reinnervation involves coaptation of residual nerve ends to nearby motor nerve branches of healthy but expendable muscles proximal to an amputation. It has been shown to prevent and reduce residual limb pain and phantom limb pain after major upper and lower extremity amputation. However, the use of this technique has not been described distal to the forearm because bioprosthetic use is not a consideration at that level. The aim of this article was to (1) present 2 cases of TMR performed in the setting of ray amputation, and (2) provide technical strategies for maximizing success and efficiency.

The Impact of Surgical Amputation and Valproic Acid on Pain and Functional Trajectory: Results from the Veterans Integrated Pain Evaluation Research (VIPER) Randomized, Double-Blinded Placebo-Controlled Trial.

OBJECTIVE: To determine if the perioperative administration of valproic acid reduces the incidence of chronic pain three months after amputation or revision surgery. DESIGN: Multicenter, randomized, double-blind, placebo-controlled trial. SETTING: Academic, military, and veteran medical centers. SUBJECTS: One hundred twenty-eight patients undergoing amputation or amputation revision surgery at Duke University Hospital, Walter Reed National Military Medical Center, or the Durham Veterans Affairs Medical Center for either medical disease or trauma. METHODS: Patients were randomized to placebo or valproic acid for the duration of hospitalization and treated with multimodal analgesic care, including regional anesthetic blockade. Primary outcome was the proportion of patients with chronic pain at three months (average numeric pain score intensity of 3/10 or greater). Secondary outcomes included functional trajectories (assessed with the Brief Pain Inventory short form and the Defense and Veterans Pain Rating Scale). RESULTS: The overall rate of chronic pain was 68.2% in the 107 patients who completed the end point assessment. There was no significant effect of perioperative valproic acid administration, with a rate of 65.45% (N = 36) in the treatment group and a rate of 71.15% (N = 37) in the placebo group. Overall, pain scores decreased from baseline to follow-up (median = -2 on the numeric pain scale). Patients additionally experienced improvements in self-perceived function. CONCLUSIONS: The rate of chronic pain after amputation surgery is not significantly improved with the perioperative administration of valproic acid. In this cohort treated with multimodal perioperative analgesia and regional anesthetic blockade, we observed improvements in both pain severity and function.

The Preventive Value of Epidural Calcitonin in Patients with Lower Limb Amputation.

BACKGROUND: Postamputation pain is highly prevalent after limb amputation with neuropathic nature; calcitonin may effectively relieve many neuropathic pain states. DESIGN: Double-blind randomized multicenter study. SETTING: Our study hypothesis is to evaluate the preventive value of epidural calcitonin on postoperative pain, grade of phantom pain, and the development of allodynia and hyperalgesia in patients undergoing lower limb amputation. PATIENTS: A cohort of 60 diabetic patients of both genders suffering from vascular insufficiency of one or both lower limbs underwent minor or major lower limb amputation. Patients were divided randomly into two equal groups: an epidural bupivacaine-calcitonin-fentanyl (BCF) group and a bupivacaine-fentanyl (BF) group. METHODS: Patients were instructed about the use of a 10 cm visual analog scale (VAS). Phantom limb pain was graded using a four-grade scale. Pin-prick hyperalgesia and allodynia were evaluated at one week, one month, three months, and six months after surgery. RESULTS: There were no significant differences between groups regarding patients' characteristics. There was no significant difference in the VAS scale between groups. There was statically significant improvement in the grade of phantom pain in the BCF group at six and 12 months after surgery ( P = 0.033 and 0.001, respectively). A significantly higher number of patients developed allodynia in the BF group at six ( P = 0.039) and 12 ( P = 0.013) months and hyperalgesia at 12 months ( P = 0.025). CONCLUSION: The preventive use of epidural calcitonin improved the grade of phantom pain and reduced the incidence of allodynia and hyperalgesia in patients undergoing lower limb amputation under combined spinal-epidural anesthesia during one year of follow-up.

Mesenchymal Stem Cell Engagement Modulates Neuroma Microenviroment in Rats and Humans and Prevents Postamputation Pain.

Postamputation pain is currently managed unsatisfactorily with neuron-targeted pharmacological and interventional therapies. Non-neuronal pain mechanisms have emerged as crucial factors in the development and persistence of postamputation pain. Consequently, these mechanisms offer exciting prospects as innovative therapeutic targets. We examined the hypothesis that engaging mesenchymal stem cells (MSCs) would foster local neuroimmune interactions, leading to a potential reduction in postamputation pain. We utilized an ex vivo neuroma model from a phantom limb pain patient to uncover that the oligodeoxynucleotide IMT504 engaged human primary MSCs to promote an anti-inflammatory microenvironment. Reverse translation experiments recapitulated these effects. Thus, in an in vivo rat model, IMT504 exhibited strong efficacy in preventing autotomy (self-mutilation) behaviors. This effect was linked to a substantial accumulation of MSCs in the neuroma and associated dorsal root ganglia and the establishment of an anti-inflammatory phenotype in these compartments. Centrally, this intervention reduced glial reactivity in the dorsal horn spinal cord, demonstrating diminished nociceptive activity. Accordingly, the exogenous systemic administration of MSCs phenocopied the behavioral effects of IMT504. Our findings underscore the mechanistic relevance of MSCs and the translational therapeutic potential of IMT504 to engage non-neuronal cells for the prevention of postamputation pain. PERSPECTIVE: The present study suggests that IMT504-dependent recruitment of endogenous MSCs within severely injured nerves may prevent post-amputation pain by modifying the inflammatory scenario at relevant sites in the pain pathway. Reinforcing data in rat and human tissues supports the potential therapeutic value of IMT504 in patients suffering postamputation pain.

"I did not expect the doctor to treat a ghost": a systematic review of published reports regarding chronic postamputation pain in British First World War veterans.

Limb trauma remains the most prevalent survivable major combat injury. In the First World War, more than 700,000 British soldiers received limb wounds and more than 41,000 underwent an amputation, creating one of the largest amputee cohorts in history. Postamputation pain affects up to 85% of military amputees, suggesting that up to 33,000 British First World War veterans potentially reported postamputation pain. This qualitative systematic review explores the professional medical conversation around clinical management of chronic postamputation pain in this patient cohort, its development over the 20th century, and how this information was disseminated among medical professionals. We searched The Lancet and British Medical Journal archives (1914-1985) for reports referring to postamputation pain, its prevalence, mechanisms, descriptors, or clinical management. Participants were First World War veterans with a limb amputation, excluding civilians and veterans of all other conflicts. The search identified 9809 potentially relevant texts, of which 101 met the inclusion criteria. Reports emerged as early as 1914 and the discussion continued over the next 4 decades. Unexpected findings included early advocacy of multidisciplinary pain management, concerns over addiction, and the effect of chronic pain on mental health emerging decades earlier than previously thought. Chronic postamputation pain is still a significant issue for military rehabilitation. Similarities between injury patterns in the First World War and recent Iraq and Afghanistan conflicts mean that these historical aspects remain relevant to today's military personnel, clinicians, researchers, and policymakers.

What's New in Peripheral Nerve Stimulation.

Peripheral nerve stimulation (PNS) is a powerful interventional option for the management of otherwise intractable pain. This technique involves the implantation of electrodes to apply electrical stimulation to named peripheral nerves, thereby alleviating pain in the territory of the target nerves. Recent advancements, largely driven by physician-industry relationships, have transformed the therapy into one that is minimally invasive, safe, evidence-based, and effective. Ongoing research has expanded the indications beyond chronic neuropathic pain in a peripheral nerve distribution. This article provides an overview of recent advances in this field.

Chronic Pain Considerations in Patients with Cardiovascular Disease.

Cardiovascular disease affects close to half of the United States population and many of these patients will develop chronic pain syndromes as a result of their disease process. This article provides an overview of several pain syndromes that result, directly or indirectly, from cardiovascular disease including peripheral arterial disease, angina, thoracic outlet syndrome, postamputation pain, complex regional pain syndrome, and poststroke pain. Psychological and medical comorbidities that affect the medical decision-making process in the treatment of chronic pain associated with cardiovascular disease are also discussed.

Prevalence of postamputation pain and its subtypes: a meta-analysis with meta-regression.

INTRODUCTION: The inconsistent use of standardized approaches for classifying postamputation pain (PAP) has been a barrier to establishing its prevalence. OBJECTIVES: The primary objective of this systematic review and meta-analysis is to determine the prevalence of nontraumatic lower-extremity PAP using an established taxonomy. The secondary objective is to determine the prevalence of PAP subtypes, including phantom limb pain and residual limb pain (RLP). METHODS: An a priori protocol was registered, and a database search was conducted by a reference librarian. Randomized trials and uncontrolled studies were eligible for inclusion. The risk of bias was assessed using a tool developed for uncontrolled studies. A total of 2679 studies were screened, and 13 studies met inclusion criteria (n = 1063). RESULTS: The sources of risk of bias included selection bias and, to a lesser extent, whether the outcome was adequately ascertained. Two studies reported the prevalence of PAP and the pooled prevalence was 61% (95% confidence interval [CI], 33%-86%) with high heterogeneity (I2 = 93%). Thirteen studies reported the prevalence of phantom limb pain and the pooled prevalence was 53% (95% CI, 40%-66%) with high heterogeneity (I2 = 93%). Eight studies reported the prevalence of RLP and the pooled prevalence was 32% (95% CI 24%-41%) with high heterogeneity (I2 = 76%). Clinical subtypes of RLP were not reported. CONCLUSIONS: The prevalence of PAP is high in patients with nontraumatic lower-extremity amputations. Ongoing research that uses a taxonomy for PAP is needed to fully delineate the prevalence of PAP subtypes.

Malignant fibrous histiocytoma of the bone in a traumatic amputation stump: A case report and review of the literature.

BACKGROUND: Malignant fibrous histiocytoma (MFH) is one of the most common soft tissue sarcomas among adults. It is characterized by large size, high grade, and biological aggressiveness. There are many reports of MFH after local stimulation, such as bone fracture, implants, and chronic osteomyelitis. In this paper, we report a patient who developed MFH 6 years after amputation, suggesting that wound healing and mechanical force play a role in the local stimulation of this disease. CASE SUMMARY: A 66-year-old man complained of persistent pain in his residual mid-thigh. He had undergone amputation surgery due to a traffic accident 6 years prior. Physical examination showed tenderness but no abnormalities in appearance. X-ray radiographs and magnetic resonance imaging supported the diagnosis of a tumor, and a biopsy confirmed that the lesion was MFH. The patient received neoadjuvant chemotherapy and left hip disarticulation. During the 6-mo follow-up, there were no symptoms of recurrence. CONCLUSION: Postsurgery MFH has been reported before, and many studies have attributed it to the biological effects of implants. Our case report shows that this disease can develop without an implant and thus highlights the importance of local stimulation. The wound-healing process and mechanical force can both promote this tumor, but whether they directly cause MFH needs further investigation.

Ultrasonography-Guided Radiofrequency Ablation for Painful Stump Neuromas to Relieve Postamputation Pain: A Pilot Study.

OBJECTIVE: Postamputation pain (PAP) is a serious problem, and thus far, there is no perfect treatment strategy. Clinically, minimally invasive treatments for peripheral neuromas are simple and feasible. This study aimed to investigate the immediate and long-term effects of ultrasonography-guided radiofrequency ablation (RFA) on PAP. METHODS: Eighteen PAP subjects with painful peripheral neuromas were treated with ultrasonography-guided RFA. RESULTS: A total of 18 PAP subjects were included in the final analyses. Fourteen of the 17 subjects with residual limb pain (RLP) (82.4%) had successful outcomes. A successful outcome was noted in 9 of the 13 subjects with phantom limb pain (PLP) (69.2%). There were no significant associations between symptom relief and sex, age, or the duration of symptoms. There were no severe complications. CONCLUSIONS: Ultrasonography-guided RFA for painful stump neuromas can effectively relieve stump pain and PLP in amputees with PAP (follow-up time was 12 months). Ultrasonography-guided RFA is easy and safe and does not involve radiation exposure, making it very suitable for clinical applications.

Peripheral nerve stimulator for terminal sciatic nerve neuromas in an amputee.

Neuromas are a difficult-to-treat peripheral nerve pathology that can cause crippling pain. Optimal treatment is widely debated as pharmacological intervention frequently is not sufficient and surgical interventions are plagued with recurrence. The majority of amputees report severe and chronic stump pain. Avoiding complex surgery at the stump site would prevent infection or wound dehiscence. Recent advances in neuromodulation with external pulse emitters allow for pain relief with localized nerve stimulation. The authors describe the novel placement of a sciatic nerve stimulator in a 77-year-old man for painful stump neuromas of the common peroneal and tibial nerves. The video can be found here: https://youtu.be/96kKs3qjtqc.

The Effect of Once-Daily Gabapentin Extended Release Formulation in Patients With Postamputation Pain.

OBJECTIVES: To compare gabapentin extended-release, a gastro-retentive formulation, in relieving postamputation pain among gabapentin-experienced and gabapentin-naïve patients. DESIGN: Open-labeled pilot study. SUBJECTS: Sixteen patients with postamputation pain (8 patients in the gabapentin-experienced and 8 patients in the gabapentin-naïve groups). METHODS: Patients were started on gabapentin extended-release and were followed up for 8 weeks. Patients reported their pain severity during rest and movement using a numeric rating scale (NRS), interference of pain with daily activities using the modified brief pain inventory (MBPI) questionnaire, and treatment satisfaction using the treatment satisfaction questionnaire for medication (TSQM). RESULTS: Patients from both gabapentin-experienced and gabapentin-naïve groups achieved a significant and sustainable pain relief over the course of therapy. The pain scores at rest decreased in both gabapentin-experienced and gabapentin-naïve groups from 5.88 ± 1.36 and 4.88 ± 2.95 to 1.88 ± 0.99 and 1.38 ± 1.51, respectively. An average percent of pain relief with gabapentin extended-release was noted to be significant (p < 0.01) after 8 weeks of therapy among gabapentin-experienced (81.25 ± 16.42%) and gabapentin-naïve groups (85 ± 17.73%) when compared to baseline for gabapentin-experienced (31.25 ± 29%) and gabapentin-naïve groups (36.25 ± 34.2%), respectively. Gabapentin-experienced and gabapentin-naïve groups had no significant difference in global satisfaction from treatment (79.14 ± 10.47 and 83.3 ± 20.82), convenience of treatment (73.78 ± 19.04 and 90.44 ± 11.66), effectiveness of treatment (72.6 ± 10.1 and 79.73 ± 11.6). The only statistically significant difference among gabapentin-experienced and gabapentin-naïve groups was found in adverse event tolerability (65.78 ± 10.36 and 85.8 ± 10.14, p < 0.01). CONCLUSION: Once-daily dosing of gabapentin-extended release showed significant improvement in pain severity and functional status, with no difference found between gabapentin-experienced versus gabapentin-naïve patients.

Possible inflammatory pain biomarkers in postamputation pain.

Although chronic pain after amputation is frequent, the underlying mechanisms are still not well understood. It is widely accepted that the pathogenesis of postamputation pain is multifactorial, with both peripheral and central mechanisms playing an essential role. However, recent studies suggest that the immune system plays an important role in different neuropathic pain conditions, including postamputation pain. Eleven amputees were included in this clinical study. Information on the type and intensity of spontaneous postamputation pain was obtained and evoked pain responses for brush, cold, and warm allodynia and pinprick hyperalgesia were determined. In addition, skin biopsies were taken from the amputated site and a contralateral control site and analysed for possible markers of pain: IbA1 (macrophages), calcitonin gene-related peptide (CGRP), and substance P (SP). Irrespectively of the type and intensity of postamputation pain, no differences were found in IbA1, CGRP, and SP levels between the amputated site and the control site. Although no differences between the sites were seen in this study, this new method seems promising for our understanding of skin changes in amputees. In future studies, staining for other cytokines and inflammatory mediators in skin biopsies could provide new insight into the mechanisms of postamputation pain.

Patient care for postamputation pain and the complexity of therapies: living experiences.

AIM: Limb amputation traumatically alters body image. Sensations rapidly prevail that the limb is still present and 85% of patients portray phantom limb pain. Throughout the testimonies of amputated patients with intense phantom limb pain, we show the difficulty in treating this chronic pain with current pharmacological and nonpharmacological therapies. PATIENTS & METHODS: We qualitatively analyzed the therapeutic choices of five amputees, the effectiveness of the treatments chosen and the impact on patients' quality-of-life. RESULTS & CONCLUSION: In general, patients who are refractory to pharmacological treatments are in favor of trying alternative therapies. It is therefore crucial to design a combined and personalized therapeutic plan under the coordination of a multidisciplinary team for the wellbeing of the patient.

Tibioperoneal Short Circuiting for Stump Neuroma Pain in Amputees: Revival of an Old Technique.

BACKGROUND: Stump neuroma pain in amputees can be quite challenging. Surgical treatment may be largely subdivided into neuromodulative and non-neuromodulative methods. The latter includes neurocapsis, insertion of nerve stump into the bone marrow, centro-central short circuit (CCSC), and coverage with vascularized soft tissue flaps. CCSC was shown to be extremely effective in alleviation of pain. Reports on CCSC for the treatment of stump neuroma pain have disappeared from the literature, with a shift toward neuromodulation for the treatment of pain irrespective of etiology. METHODS: We observed 8 lower limb amputees undergoing CCSC of the sciatic nerve during a follow-up of 12 years. All had the same stump neuroma pain rendering them unable to wear their prostheses. The sciatic nerve was explored at the midthigh area, much proximal to the amputation site, and a short circuit was established between the tibial and peroneal parts of the nerve. Assessment was by means of pain quantification as per the quadruple visual analogue scale, medication intake, and ability to use prostheses. RESULTS: The median worst quadruple visual analogue scale before surgery was 8.0. After surgery it decreased to 2.5 (P = 0.00094). Medication intake was reduced from regular intake of a combination of opioids, nonsteroidal anti-inflammatory drugs, tricyclic antidepressants, and pregabalin in all patients to irregular intake of nonsteroidal anti-inflammatory drug alone in 3 of 8 patients. All patients were able to wear their limb prosthesis since surgery. CONCLUSIONS: CCSC is a simple, effective, and long-lasting method to treat painful stump neuromas in amputees. It should be strongly considered in deserving cases before resorting to neuromodulative methods.