Mechanosensitive Ion Channel TMEM63A Gangs Up with Local Macrophages to Modulate Chronic Post-amputation Pain.

Post-amputation pain causes great suffering to amputees, but still no effective drugs are available due to its elusive mechanisms. Our previous clinical studies found that surgical removal or radiofrequency treatment of the neuroma at the axotomized nerve stump effectively relieves the phantom pain afflicting patients after amputation. This indicated an essential role of the residual nerve stump in the formation of chronic post-amputation pain (CPAP). However, the molecular mechanism by which the residual nerve stump or neuroma is involved and regulates CPAP is still a mystery. In this study, we found that nociceptors expressed the mechanosensitive ion channel TMEM63A and macrophages infiltrated into the dorsal root ganglion (DRG) neurons worked synergistically to promote CPAP. Histology and qRT-PCR showed that TMEM63A was mainly expressed in mechanical pain-producing non-peptidergic nociceptors in the DRG, and the expression of TMEM63A increased significantly both in the neuroma from amputated patients and the DRG in a mouse model of tibial nerve transfer (TNT). Behavioral tests showed that the mechanical, heat, and cold sensitivity were not affected in the Tmem63a-/- mice in the naïve state, suggesting the basal pain was not affected. In the inflammatory and post-amputation state, the mechanical allodynia but not the heat hyperalgesia or cold allodynia was significantly decreased in Tmem63a-/- mice. Further study showed that there was severe neuronal injury and macrophage infiltration in the DRG, tibial nerve, residual stump, and the neuroma-like structure of the TNT mouse model, Consistent with this, expression of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1ß all increased dramatically in the DRG. Interestingly, the deletion of Tmem63a significantly reduced the macrophage infiltration in the DRG but not in the tibial nerve stump. Furthermore, the ablation of macrophages significantly reduced both the expression of Tmem63a and the mechanical allodynia in the TNT mouse model, indicating an interaction between nociceptors and macrophages, and that these two factors gang up together to regulate the formation of CPAP. This provides a new insight into the mechanisms underlying CPAP and potential drug targets its treatment.

Mechanosensitive Ion Channel TMEM63A Gangs Up with Local Macrophages to Modulate Chronic Post-amputation Pain / 神经科学通报·英文版

Post-amputation pain causes great suffering to amputees, but still no effective drugs are available due to its elusive mechanisms. Our previous clinical studies found that surgical removal or radiofrequency treatment of the neuroma at the axotomized nerve stump effectively relieves the phantom pain afflicting patients after amputation. This indicated an essential role of the residual nerve stump in the formation of chronic post-amputation pain (CPAP). However, the molecular mechanism by which the residual nerve stump or neuroma is involved and regulates CPAP is still a mystery. In this study, we found that nociceptors expressed the mechanosensitive ion channel TMEM63A and macrophages infiltrated into the dorsal root ganglion (DRG) neurons worked synergistically to promote CPAP. Histology and qRT-PCR showed that TMEM63A was mainly expressed in mechanical pain-producing non-peptidergic nociceptors in the DRG, and the expression of TMEM63A increased significantly both in the neuroma from amputated patients and the DRG in a mouse model of tibial nerve transfer (TNT). Behavioral tests showed that the mechanical, heat, and cold sensitivity were not affected in the Tmem63a-/- mice in the naïve state, suggesting the basal pain was not affected. In the inflammatory and post-amputation state, the mechanical allodynia but not the heat hyperalgesia or cold allodynia was significantly decreased in Tmem63a-/- mice. Further study showed that there was severe neuronal injury and macrophage infiltration in the DRG, tibial nerve, residual stump, and the neuroma-like structure of the TNT mouse model, Consistent with this, expression of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β all increased dramatically in the DRG. Interestingly, the deletion of Tmem63a significantly reduced the macrophage infiltration in the DRG but not in the tibial nerve stump. Furthermore, the ablation of macrophages significantly reduced both the expression of Tmem63a and the mechanical allodynia in the TNT mouse model, indicating an interaction between nociceptors and macrophages, and that these two factors gang up together to regulate the formation of CPAP. This provides a new insight into the mechanisms underlying CPAP and potential drug targets its treatment.

Evidence-Based Clinical Guidelines from the American Society of Pain and Neuroscience for the Use of Implantable Peripheral Nerve Stimulation in the Treatment of Chronic Pain.

The objective of this peripheral nerve stimulation consensus guideline is to add to the current family of consensus practice guidelines and incorporate a systematic review process. The published literature was searched from relevant electronic databases, including PubMed, Scopus, Cochrane Central Register of Controlled Trials, and Web of Science from database inception to March 29, 2021. Inclusion criteria encompassed studies that described peripheral nerve stimulation in patients in terms of clinical outcomes for various pain conditions, physiological mechanism of action, surgical technique, technique of placement, and adverse events. Twenty randomized controlled trials and 33 prospective observational studies were included in the systematic review process. There is Level I evidence supporting the efficacy of PNS for treatment of chronic migraine headaches via occipital nerve stimulation; chronic hemiplegic shoulder pain via stimulation of nerves innervating the trapezius, supraspinatus, and deltoid muscles; failed back surgery syndrome via subcutaneous peripheral field stimulation; and lower extremity neuropathic and lower extremity post-amputation pain. Evidence from current Level I studies combined with newer technologies facilitating less invasive and easier electrode placement make peripheral nerve stimulation an attractive alternative for managing patients with complex pain disorders. Peripheral nerve stimulation should be used judiciously as an adjunct for chronic and acute postoperative pain following adequate patient screening and positive diagnostic nerve block or stimulation trial.

Multicenter, Double-Blinded, Randomized, Active-Sham Controlled Clinical Study Design to Assess the Safety and Effectiveness of a Novel High Frequency Electric Nerve Block System in the Treatment of Post-Amputation Pain (The QUEST Study).

Background: Chronic pain that follows amputation of a limb is reported as "one of the most severe pains in the human experience," due to the magnitude of tissue injury and the multiple potential of pain generators at the local peripheral, spinal, and cortical levels. The Altius® System was developed to deliver high-frequency nerve block (HFNB) therapy via a cuff electrode applied to the peripheral nerve(s) and an implantable pulse generator. We report a novel clinical trial design for the first study of an active-implantable medical device in subjects with lower-limb post-amputation pain utilizing a multicenter, double-blinded, randomized, active-sham controlled clinical study protocol called QUEST, which is an ongoing investigational device exemption study to support United States Food and Drug Administration approval. Methods: The study enrollment of 180 subjects was completed in September 2021. Subjects were randomized 1:1 to the treatment group or the active-sham control group for the 3-month primary effectiveness and safety endpoints. After month 3, the active-sham control program group crossed over to the treatment program group and all subjects continued to the 12-month study endpoint. Study effectiveness success is determined by a superiority test between responder rates in the treatment and control groups at 3 months. A responder is defined as someone who experiences a 50% or greater reduction in pain scores - after a 30-minute treatment session - for more than 50% of all pain episodes in which the treatment was used. Discussion: The QUEST study design employs an active-sham control group to objectively assess the effectiveness of HFNB therapy. Additionally, the electronic diary repeated measures data collection in QUEST is expected to reduce the intra-subject variation typically observed in pain treatment studies. Finally, the longitudinal measurement of health-related quality of life and use of pain medication may, for example, show effectiveness in reducing opioid use over time.

Post-amputation pain among lower limb amputees in a tertiary care hospital in Jeddah, Saudi Arabia: A retrospective study.

OBJECTIVES: To estimate the prevalence of post- amputation pain among lower-limb amputees and its burden on their lives. METHODS: A retrospective patients record review of lower limb amputation surgeries was carried out at King Abdulaziz University Hospital, Jeddah, Saudi Arabia, between 2008-2019. e collected data included: patients demographics, surgical operations, chronic pain characteristics, functional impairment, and treatment. RESULTS: A total of 645 lower-limb amputations carried out on 509 patients, 104 (20.4%) patients had more than one amputation surgery carried out, and 40 (7.9%) patients having bilateral amputations. The estimated prevalence of chronic post-amputation pain among the lower-limb amputees was approximately 61.5%. Persistent postoperative neuropathic pain was the most common type of pain following amputation, followed by residual limb pain, then phantom limb pain. The most common cause of amputation was diabetes and its related complications (76%). The mean age at surgery was 57.46±12.02 years. Although diabetes was a common comorbid illness (95.6%), it had no correlation with the development of chronic post-amputation pain. However, peripheral vascular disease had a strong association (p=0.009), especially with the development of phantom limb pain (54.5%; p=0.016). The most common reason for functional impairment among the amputees was disability (52.7%), while only 6.6% said it was secondary to pain. CONCLUSION: Post-amputation pain is one of the major consequences of amputation. Pain was poorly managed among these patients. Special considerations should be obtained to manage these patients' pain and reduce their suffering.

The effect of post-amputation pain on health-related quality of life in lower limb amputees.

PURPOSE: There is conflicting literature on the effect of post-amputation pain on quality of life (QOL) and no available literature on the relationship of pain medications to QOL of amputees in pain. The aims of the study were to compare QOL in lower limb amputees with significant pain to those with minimal pain and compare QOL in amputees on multiple pain medications (≥3 and/or ≥ 40 mg morphine equivalent/day) to those on minimal. METHODS: Cross-sectional study of amputees (n = 101) utilizing standardized (brief pain inventory, pain self-efficacy, Euro QOL scale), institutional amputee specific questionnaires. RESULTS: Post-amputation pain was common (69%), but only 13% of the participants were using more pain medications. High-pain interference and poor self-efficacy were associated with poorer QOL after adjusting for age, gender and cause of amputation. High medication use was associated with high-pain interference and poor self-efficacy, but there was minimal correlation between pain scores and medication usage (p > 0.05). Quality of life was not influenced by high medication usage (p > 0.05 for pain interference; p > 0.05 for self-efficacy). CONCLUSION: Post-amputation pain continues to be a major determinant of QOL in lower limb amputees, but the role of pain medications on an amputee's QOL remains unclear.IMPLICATIONS FOR REHABILITATIONAn amputee's QOL is affected by the severity of their post-amputation pain even beyond six months post their amputation.An amputee with more pain may not necessarily take more pain medications to manage their pain. The amount of pain medications taken may not influence their self-reported QOL.Pain and QOL assessment should be integrated into routine clinical evaluation of adult amputees. Standardized screening tools and/or formative assessment can be utilized for assessing QOL.

Management of Post-Amputation Pain.

INTRODUCTION: The prevalence of amputation and post-amputation pain (PAP) is rising. There are two main types of PAP: residual limb pain (RLP) and phantom limb pain (PLP), with an estimated 95% of people with amputations experiencing one or both. Medical Management: The majority of chronic PAP is due to phantom limb pain, which is neurogenic in nature. Common medications used include tricyclic antidepressants, gabapentin, and opioids. Newer studies are evaluating alternative drugs such as ketamine and local anesthetics. Rehabilitation Management: Mirror visual feedback and cognitive behavioral therapy are often effective adjunct therapies and have minimal adverse effects. Surgical Management: Neuromodulatory treatment and surgery for neuromas have been found to help select patients with PAP. CONCLUSION: PAP is a complex condition with mechanisms that can be located at the residual limb, spinal cord, and brain - or a combination. This complex pain can be difficult to treat. The mainstays of treatment are largely medical, but several surgical options are also being studied.

Percutaneous 60-day peripheral nerve stimulation implant provides sustained relief of chronic pain following amputation: 12-month follow-up of a randomized, double-blind, placebo-controlled trial.

INTRODUCTION: Peripheral nerve stimulation (PNS) has historically been used to treat chronic pain, but generally requires implantation of a permanent system for sustained relief. A recent study found that a 60-day PNS treatment decreases post-amputation pain, and the current work investigates longer-term outcomes out to 12 months in the same cohort. METHODS: As previously reported, 28 traumatic lower extremity amputees with residual and/or phantom limb pain were randomized to receive 8 weeks of PNS (group 1) or 4 weeks of placebo followed by a crossover 4 weeks of PNS (group 2). Percutaneous leads were implanted under ultrasound guidance targeting the femoral and sciatic nerves. During follow-up, changes in average pain and pain interference were assessed using the Brief Pain Inventory-Short Form and comparing with baseline. RESULTS: Significantly more participants in group 1 reported ≥50% reductions in average weekly pain at 12 months (67%, 6/9) compared with group 2 at the end of the placebo period (0%, 0/14, p=0.001). Similarly, 56% (5/9) of participants in group 1 reported ≥50% reductions in pain interference at 12 months, compared with 2/13 (15%, p=0.074) in group 2 at crossover. Reductions in depression were also statistically significantly greater at 12 months in group 1 compared with group 2 at crossover. CONCLUSIONS: This work suggests that percutaneous PNS delivered over a 60-day period may provide significant carry-over effects including pain relief, potentially avoiding the need for a permanently implanted system while enabling improved function in patients with chronic pain. TRIAL REGISTRATION NUMBER: NCT01996254.

Pain management in new amputees: a nursing perspective.

Phantom limb pain (PLP) is a widespread and challenging neuropathic pain problem, occurring after both surgical and traumatic amputation of a limb. It may occur immediately after surgery or some months later, however, most cases it presents within the first 7 postoperative days. Patients report a range of pain characteristics in the absent limb, including burning, cramping, tingling and electric shock sensation. The incidence of PLP has been reported to be between 50% and 85% following amputation. Its management is notoriously difficult, with no clear consensus on optimal treatment. It is often resistant to classic balanced analgesia and typical neuropathic pain medications. Taking into account these issues, the authors aimed to improve the management of patients undergoing amputation at their institution, by ensuring accurate and holistic assessment, the selection of suitable interventions through critical analysis and synthesis of available evidence, and the appropriate evaluation and adaptation of treatment plans, to ensure patients achieved their individualised goals.

Percutaneous Peripheral Nerve Stimulation for the Treatment of Chronic Pain Following Amputation.

INTRODUCTION: Chronic pain and reduced function are significant problems for Military Service members and Veterans following amputation. Peripheral nerve stimulation (PNS) is a promising therapy, but PNS systems have traditionally been limited by invasiveness and complications. Recently, a novel percutaneous PNS system was developed to reduce the risk of complications and enable delivery of stimulation without surgery. MATERIALS AND METHODS: Percutaneous PNS was evaluated to determine if stimulation provides relief from residual and phantom limb pain following lower-extremity amputation. PNS leads were implanted percutaneously to deliver stimulation to the femoral and/or sciatic nerves. Patients received stimulation for up to 60 days followed by withdrawal of the leads. RESULTS: A review of recent studies and clinical reports found that a majority of patients (18/24, 75%) reported substantial (≥50%) clinically relevant relief of chronic post-amputation pain following up to 60 days of percutaneous PNS. Reductions in pain were frequently associated with reductions in disability and pain interference. CONCLUSIONS: Percutaneous PNS can durably reduce pain, thereby enabling improvements in quality of life, function, and rehabilitation in individuals with residual or phantom limb pain following amputation. Percutaneous PNS may have additional benefit for Military Service members and Veterans with post-surgical or post-traumatic pain.

Percutaneous peripheral nerve stimulation for the treatment of chronic neuropathic postamputation pain: a multicenter, randomized, placebo-controlled trial.

BACKGROUND AND OBJECTIVES: Chronic neuropathic pain is a common challenging condition following amputation. Recent research demonstrated the feasibility of percutaneously implanting fine-wire coiled peripheral nerve stimulation (PNS) leads in proximity to the sciatic and femoral nerves for postamputation pain. A multicenter, double-blinded, randomized, placebo-controlled study collected data on the safety and effectiveness of percutaneous PNS for chronic neuropathic pain following amputation. METHODS: Twenty-eight lower extremity amputees with postamputation pain were enrolled. Subjects underwent ultrasound-guided implantation of percutaneous PNS leads and were randomized to receive PNS or placebo for 4 weeks. The placebo group then crossed over and all subjects received PNS for four additional weeks. The primary efficacy endpoint evaluated the proportion of subjects reporting ≥50% pain reduction during weeks 1-4. RESULTS: A significantly greater proportion of subjects receiving PNS (n=7/12, 58%, p=0.037) demonstrated ≥50% reductions in average postamputation pain during weeks 1-4 compared with subjects receiving placebo (n=2/14, 14%). Two subjects were excluded from efficacy analysis due to eligibility changes. Significantly greater proportions of PNS subjects also reported ≥50% reductions in pain (n=8/12, 67%, p=0.014) and pain interference (n=8/10, 80%, p=0.003) after 8 weeks of therapy compared with subjects receiving placebo (pain: n=2/14, 14%; pain interference: n=2/13, 15%). Prospective follow-up is ongoing; four of five PNS subjects who have completed 12-month follow-up to date reported ≥50% pain relief. CONCLUSIONS: This work demonstrates that percutaneous PNS therapy may provide enduring clinically significant pain relief and improve disability in patients with chronic neuropathic postamputation pain. TRIAL REGISTRATION NUMBER: NCT01996254.

Selective Radiofrequency Stimulation of the Dorsal Root Ganglion (DRG) as a Method for Predicting Targets for Neuromodulation in Patients With Post Amputation Pain: A Case Series.

OBJECTIVE: While spinal cord stimulation (SCS) has established itself as an accepted and validated treatment for neuropathic pain, there are a number of conditions where it has experienced less, long-term success: post amputee pain (PAP) being one of them. Dorsal root ganglion (DRG) stimulation has shown great promise, particularly in conditions where traditional SCS has fallen short. One major difference between DRG stimulation and traditional SCS is the ability to provide focal stimulation over targeted areas. While this may be a contributing factor to its superiority, it can also be a limitation insofar stimulating the wrong DRG(s) can lead to failure. This is particularly relevant in conditions like PAP where neuroplastic maladaptation occurs causing the pain to deviate from expected patterns, thus creating uncertainty and variability in predicting targets for stimulation. We propose selective radiofrequency (RF) stimulation of the DRG as a method for preoperatively predicting targets for neuromodulation in patients with PAP. METHODS: We present four patients with PAP of the lower extremities. RF stimulation was used to selectively stimulate individual DRG's, creating areas of paresthesias to see which most closely correlated/overlapped with the painful area(s). RF stimulation to the DRG's that resulted in the desirable paresthesia coverage in the residual or the missing limb(s) was recorded as "positive." Trial DRG leads were placed based on the positive RF stimulation findings. RESULTS: In each patient, stimulating one or more DRG(s) produced paresthesias patterns that were contradictory to know dermatomal patterns. Upon completion of a one-week trial all four patients reported 60-90% pain relief, with coverage over the painful areas, and opted for permanent implant. CONCLUSIONS: Mapping the DRG via RF stimulation appears to provide improved accuracy for determining lead placement in the setting of PAP where pain patterns are known to deviate from conventional dermatomal mapping.

Ultrasound-guided alcohol neurolysis and radiofrequency ablation of painful stump neuroma: effective treatments for post-amputation pain.

BACKGROUND: Post-amputation pain (PAP) is highly prevalent after limb amputation, and stump neuromas play a key role in the generation of the pain. Presently, PAP refractory to medical management is frequently treated with minimally invasive procedures guided by ultrasound, such as alcohol neurolysis and radiofrequency ablation (RFA). OBJECTIVE: To record the immediate and long-term efficacy of alcohol neurolysis and RFA. We first used alcohol neurolysis and then, when necessary, we performed RFA on PAP patients. STUDY DESIGN: Prospective case series. SETTING: Pain management center. METHODS: Thirteen subjects were treated with ultrasound-guided procedures. RESULTS: All patients were treated with neurolysis using alcohol solutions guided by ultrasound. Seven (54%) of 13 subjects achieved pain relief after 1-3 alcohol injection treatments. The remaining 6 subjects obtained pain relief after receiving 2 administrations of ultrasound-guided RFA. After a 6-month follow-up evaluation period, pain quantities were also assessed. Both stump pain (including intermittent sharp pain and continuous burning pain) and phantom pain were relieved. The frequency of intermittent sharp pain was decreased, and no complications were noted during the observation. CONCLUSION: The use of ultrasound guidance for alcohol injection and RFA of painful stump neuromas is a simple, radiation-free, safe, and effective procedure that provides sustained pain relief in PAP patients. In this case series, RFA was found to be an effective alternative to alcohol injection.