Interim Findings on Phantom Limb Pain Syndrome Features across Age Groups Following Limb Amputation for Malignancy

Targeted Muscle Reinnervation (TMR) at Time of Major Amputation Decreases Phantom and Residual Limb Pain

Chronic phantom sensations, phantom pain, residual limb pain, and other regional pain after lower limb amputation

ONE potential adverse outcome from surgery is chronic pain. Analysis of predictive and pathologic factors is important to develop rational strategies to prevent this problem. Additionally, the natural history of patients with and without persistent pain after surgery provides an opportunity to improve the understanding of the physiology and psychology of chronic pain. Ideally, studies of chronic postoperative pain should include (1) sufficient preoperative data (assessment of pain, physiologic and psychologic risk factors for chronic pain); (2) detailed descriptions of the operative approaches used (location and length of incisions, handling of nerves and muscles); (3) the intensity and character of acute postoperative pain and its management; and (4) follow-up at intervals to 1 yr or more. In addition, there would be information about postoperative interventions that may influence pain, such as radiation therapy or chemotherapy. At long-term follow-up visits, patient function, physical signs, and symptoms would be evaluated using a standardized algorithm, including quantitative and descriptive pain assessments. We found no studies that contain all of these data. For this review, we specifically sought population data that reflect the incidence of chronic postoperative pain or predictors (medical, physiologic, and psychologic) of chronic pain. We selected five groups of surgeries (limb amputations, breast surgery, gallbladder surgery, lung surgery, and inguinal hernia surgery). These surgeries were selected because the incidence of pain is known to be high, thus improving the probability of detecting predictive factors. They also represent a range of major surgical procedures.

This study describes the sensations and pain reported by persons with unilateral lower extremity amputations. Participants (n = 92) were recruited from two hospitals to complete the Prosthesis Evaluation Questionnaire which included questions about amputation related sensations and pain. Using a visual analog scale, participants reported the frequency, intensity, and bothersomeness of phantom limb, residual limb, and back pain and nonpainful phantom limb sensations. A survey of medication use for each category of sensations also was included. Statistical analyses revealed that nonpainful phantom limb sensations were common and more frequent than phantom limb pain. Residual limb pain and back pain were also common after amputation. Back pain surprisingly was rated as more bothersome than phantom limb pain or residual limb pain. Back pain was significantly more common in persons with above knee amputations. These results support the importance of looking at pain as a multidimensional rather than a unidimensional construct. They also suggest that back pain after lower extremity amputation may be an overlooked but very important pain problem warranting additional clinical attention and study.

Targeted Brain Rehabilitation: Development, Feasibility, and Usability of a Novel Virtual Reality System for Phantom Limb Pain Management and Amputee Rehabilitation.

Preemptive Treatment of Phantom and Residual Limb Pain with Targeted Muscle Reinnervation at the Time of Major Limb Amputation

Virtual reality therapies for phantom limb pain.

Many amputees are left with chronic localized pain, centralized pain, and phantom limb pain or sensation, often resulting from neuromas in the residual limb. Historically, there is no reliably effective intervention for pain associated with neuroma-related residual or phantom limb pain. Targeted muscle reinnervation (TMR) is a surgical procedure first described in 2002 that involves the transfer of residual nerves from amputated limbs to new muscle targets. TMR has been shown to significantly reduce neuroma pain and facilitate the use of prostheses. A prospective study was conducted of 61 patients who underwent TMR for neuroma treatment or prevention between 2017 and 2022. Primary outcomes included overall, phantom, and residual limb pain recorded using the Visual Analog Scale (VAS), as well as Patient-Reported Outcomes Measurement Information System (PROMIS) forms for Pain Intensity, Quality, Interference, and Behavior. Retrospective data was collected for a propensity-matched cohort of non-TMR amputees to compare pain outcomes. TMR was performed for 25 upper extremity and 35 lower extremity amputations, and 5 patients underwent TMR on multiple limbs. Significant reductions were observed in overall limb pain (-3.2 points), phantom limb pain (-2.6 points), and residual limb pain (-3.0 points) for the TMR cohort. Mean PROMIS scores for TMR patients were 49.7 for Pain Intensity, 54.0 for Pain Quality, 55.3 for Pain Interference, and 56.1 for Pain Behavior. At the 8.4-month follow-up, 43.8% of TMR patients (vs 84% of controls) remained on neuromodulators, opioids, or both, for pain control. TMR improved phantom and residual limb pain in amputees, as evidenced by clinically and statistically significant reductions in pain with reduced need for long-term opioids and/or neuromodulators. These findings support the current understanding of TMR but underscore the need for continued investigation to comprehensively assess the potential of this promising technique in improving the functional outcomes and quality of life in the amputee population.

This article is accompanied by the following Invited Commentary: Wittmann M, Matot I, Hoeft A. ESA Clinical Trials Network 2012. Eur J Anaesthesiol 2013; 30:208–210. The number of patients suffering from critical limb ischaemia is large and growing. For the population aged 60 to 90 years, the prevalence is estimated at 1% and increasing.1 Current literature suggests that about 25% of these patients will need to undergo amputation.2 Even with the increased use of interventional treatment of vascular disease, amputation remains a frequently performed procedure and for the United States alone, current projections estimate that the number of patients living with loss of a limb due to vascular disease will rise from the current number of 850 000 to 2 200 000 by the year 2050.3 The prevalence of phantom pain following surgical amputation is high. A recent study confined to patients undergoing lower limb amputation for peripheral vascular disease reported phantom limb pain in 79% of patients.4 Several studies have addressed the potential of analgesic interventions to reduce the incidence of chronic phantom pain. However, these have been hampered by small numbers of patients, and heterogeneous patient groups. A recent systematic review by Ypsilantis and Tang5 concluded that robust evidence to support a positive impact of anaesthetic interventions in the prevention of phantom limb pain is, to date, lacking. In a randomised controlled trial conducted by Karanikolas et al.,6 it was suggested that strict perioperative pain control using fixed regimens of nonopioid analgesics and patient-controlled opiate analgesia could reduce the incidence of phantom limb pain from 75 to 53%. Pilot studies investigating preventive effects of peripheral nerve blockade have shown conflicting results.7,8 Borghi et al.9 reported their experience in 71 patients treated with an elastomeric infusion system connected to a sciatic nerve catheter in place for a median duration of 1 month. Here, the incidence of phantom limb pain was 15%, and phantom limb sensations were present in 39% after 12 months. However, the incidence of severe phantom limb pain was only 3%. Therefore, peripheral nerve blockade may represent a safe and effective option to prevent phantom limb pain, but no adequately powered prospective randomised trial has investigated this possibility. Why certain patients develop ongoing pain postoperatively while in others, the pain resolves, is largely unknown and, to date, unpredictable, and is the reason for a genetic component of this study. Recent mono-zygotic versus dizygotic twin studies show that heritable components contribute up to two-thirds of the risk of developing chronic pain.10 Such data clearly suggest a genetic predisposition for the development of chronic pain. An additional aim of the present study is to advance identification of these genetic factors. This study is designed to compare two interventions thought to contribute to a decreased incidence of phantom limb pain (strict intravenous pain control versus strict intravenous pain control along with peripheral nerve block). There are two main research questions. First, under optimised intravenous perioperative analgesia, what is the incidence of chronic phantom limb pain 12 months after transtibial amputation for peripheral vascular disease? Second, what is the value of continuous sciatic nerve block added to optimised perioperative analgesia in patients undergoing transtibial amputation for peripheral vascular disease? The aim of the study is to test the hypothesis that a combination of optimised intravenous pain therapy and continuous sciatic nerve block decreases the prevalence of phantom limb pain 12 months after transtibial amputation for peripheral vascular disease when compared with optimised intravenous pain therapy alone. The study is interventional, prospective, randomised and double-blinded (blinding of patient and physician). Online computer-based randomisation, stratified according to planned anaesthetic technique (spinal/general anaesthesia), will be used. Previous outcome studies investigating the effect of optimised perioperative analgesia alone have indicated a prevalence of phantom limb pain 1 year after amputation of 45%.6 A meaningful clinical effect will be assumed when the prevalence of phantom limb pain 12 months after amputation can be reduced from 45 to 30%. Taking an alpha level of 0.05 and a power of 80%, the estimated sample size per group is 163 patients; assuming a drop-out rate of approximately 20%, the trial will recruit 163/0.8 = 200 patients per treatment group. The primary efficacy variable is the prevalence of chronic phantom limb pain at 12 months. This variable will be presented for both treatment groups as proportions together with 95% confidence intervals. Logistic regression analyses will be performed to assess the effect of potential influential variables such as single nucleotide polymorphisms, preamputation pain and surgical technique. The last observation carried forward procedure will be applied in case of withdrawals. For the intention-to-treat analysis, the incidence of phantom limb pain at 7 days, 1 and 6 months will be carried forward to 1 year in case the (1-year) observation is missing. The aim is to recruit a total of 10 to 15 centres through the European Society of Anaesthesiology Clinical Trial Network. We aim to generate a network of hospitals performing approximately 400 transtibial amputations for peripheral vascular disease per year. Assuming a 50% inclusion rate and a desired inclusion of 400 patients, the recruitment period is predicted to last between 2 and 2.5 years, followed by 1-year follow-up. Thus, including follow-up, the study is projected to last for an estimated 3.5 years. Patients undergoing elective transtibial amputation for peripheral vascular disease, aged more than 18 years and with the American Society of Anesthesiologists' (ASA) status II to IV, will be included. We will exclude patients with a contraindication to peripheral regional anaesthesia, allergy to local anaesthetics, prior amputation resulting in current phantom limb pain, severe psychiatric disease, pregnancy or breastfeeding amputation for tumour surgery, traumatic amputation and inability of the patient to give written and informed consent. All patients will receive 'optimised intravenous pain control'. The key components of this regimen are the administration of low-dose ketamine, patient-controlled analgesia using strong opioids, and the use of nonopioids (for example paracetamol and/or metamizol). A sciatic nerve catheter will be inserted using ultrasound guidance preoperatively in all patients. Patients will receive general or spinal anaesthesia at the discretion of the treating physician. Global anaesthesia parameters will be recorded. Surgical methods are at the discretion of the treating surgeon, but will be recorded. The only interventions and standardisations will be those performed in relation to perioperative pain therapy. According to their randomisation, patients will follow one of the two standardised pain therapy regimens until 1 week postoperatively: optimised intravenous treatment ('Control', n = 200) with administration of isotonic saline via the sciatic nerve catheter; or optimised intravenous treatment along with sciatic nerve block ('Intervention', n = 200) with administration of a local anaesthetic via the sciatic nerve catheter. For all patients, participation in this study results in a thorough and continuous evaluation and strict treatment of perioperative pain. For ethical reasons, a true 'conventional' pain control group as described in previous trials (opioids administered intramuscularly or subcutaneously as needed, no strict control of pain scores and therapy) will not be included in the present study because these groups have featured excessive pain scores and a very high probability of chronic phantom limb pain.6,11 Data entries will be made on a paper version of the case report form. These will then be transferred to an electronic case report form (eCRF) in the OpenClinica software (Waltham, Massachusetts, USA). All investigators will 'log-in' with a personal code. All changes or additions to the data are tracked by the data management system in the audit trail. Access to the data entry system and eCRF is managed by the European Society of Anaesthesiology Research Office and protected by a personalised user name and password. The primary outcome measure is the prevalence of phantom limb pain 12 months postoperatively defined (yes/no) as follows: pain in the amputated area of the limb with a corresponding numerical rating scale score of at least 2 during the preceding 4 weeks (constant or at least three episodes) or ingestion of drugs administered specifically to treat phantom limb pain (classified as none, nonopioid, weak opioid, strong opioid, antidepressant, anticonvulsant, other). Selected secondary outcome measures include the incidence of phantom limb pain at 7 days, 1 and 6 months; McGill Pain Questionnaire (short-form MPQ) preoperatively and postoperatively at day 7, and 1, 6 and 12 months postoperatively; SF-12 quality of life score; overall benefit of analgesia score (OBAS) during the first postoperative week; recording of surgical handling of nerves and surgical technique; and genotype of patients assessed preoperatively. Gene haplotype will be assayed for association with acute to chronic pain conversion using single nucleotide polymorphisms from known risk factor genes including GCH1, KCNS1, Nav1.7 and P2X7R.12 This study will be conducted by the Academic Medical Center, University of Amsterdam (sponsor) and will be supported by the Clinical Trial Network, European Society of Anaesthesiology. The aim is to make a scientific case for or against the routine use of perioperative peripheral nerve blockade to prevent phantom limb pain after transtibial amputations. Acknowledgements Assistance with the article: none declared. Financial support and sponsorship: the study is funded by the European Society of Anaesthesiology (ESA). Submitted on behalf of the members of the Steering Committee: D.A. Legemate (Department of Surgery, Academic Medical Center, University of Amsterdam, The Netherlands), F. Nollet (Department of Rehabilitation Medicine, Academic Medical Center, University of Amsterdam, The Netherlands), H. Ulmer (Department of Medical Statistics, Informatics and Health Economics, Innsbruck Medical University, Austria) and J.P. Rathmell (Center for Pain Medicine, Department of Anaesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA). Conflicts of interest: none declared. Comment from the Editor: this article was checked by the editors but was not sent for external peer review.

Phantom limb and complex regional pain syndrome type 1 (CRPS1) are characterized by changes in cortical processing and organization, perceptual disturbances, and poor response to conventional treatments. Graded motor imagery is effective for a small subset of patients with CRPS1. To investigate whether graded motor imagery would reduce pain and disability for a more general CRPS1 population and for people with phantom limb pain. Fifty-one patients with phantom limb pain or CRPS1 were randomly allocated to motor imagery, consisting of 2 weeks each of limb laterality recognition, imagined movements, and mirror movements, or to physical therapy and ongoing medical care. There was a main statistical effect of treatment group, but not diagnostic group, on pain and function. The mean (95% CI) decrease in pain between pre- and post-treatment (100 mm visual analogue scale) was 23.4 mm (16.2 to 30.4 mm) for the motor imagery group and 10.5 mm (1.9 to 19.2 mm) for the control group. Improvement in function was similar and gains were maintained at 6-month follow-up. Motor imagery reduced pain and disability in these patients with complex regional pain syndrome type I or phantom limb pain, but the mechanism, or mechanisms, of the effect are not clear.

The relationship between phantom limb phenomena and cortical reorganization was examined in five subjects with congenital absence of an upper limb and nine traumatic amputees. Neuromagnetic source imaging revealed minimal reorganization of primary somatosensory cortex in the congenital amputees (M=0.69 cm, SD 0.24) and the traumatic amputees without phantom limb pain (M=0.27 cm, SD 0.25); the amputees with phantom limb pain showed massive cortical reorganization (M=2.22 cm, SD 0.78). Phantom limb pain and nonpainful phantom limb phenomena were absent in the congenital amputees. Whereas phantom limb pain was positively related to cortical reorganization (r=0.87), nonpainful phantom phenomena were not significantly correlated with cortical reorganization (r=0.34). Sensory discrimination was normal and mislocalization (referral of stimulation-induced sensation to a phantom limb) was absent in the congenital amputees. The role of peripheral and central factors in the understanding of phantom limb pain and phantom limb phenomena is discussed in view of these findings.

Case seriesPatients:—Final Diagnosis: Post-amputation phantom limb painSymptoms: Phantom limb painMedication: —Clinical Procedure: —Specialty: AnesthesiologyObjective:Unusual or unexpected effect of treatmentBackground:Postamputation phantom and residual limb pain are common and frequently intractable, with few reliably effective treatments. Pulsed nonthermal shortwave (radiofrequency) electromagnetic field therapy is a noninvasive treatment used previously as an adjunct analgesic and wound healing therapy. Its use for postamputation pain remains unexamined.Case Reports:Twelve patients with an above or below knee amputation with persistent, intractable phantom and/or residual limb pain unresponsive to multiple previous invasive treatments were provided with a noninvasive, wearable, pulsed electromagnetic field device (RecoveryRx, BioElectronics Corporation, Frederick, MD, USA). Patients used the included dressings to self-apply the 12 cm-diameter ringed antenna to their residual limb and then activated the device, which delivered nonthermal radiofrequency energy continuously for up to 30 days. Of the 12 individuals, 4 (33%) experienced minimal/no change, 7 (58%) rated their phantom and/or residual limb pain as “very much improved” at the conclusion of treatment, and 1 (8%) patient reported “moderate” improvement, using the Patient Global Impression of Change scale. Of the 8 responders, worst and average phantom limb pain improved a mean (SD) of 4.0 (2.9) and 4.2 (1.8) points on the 0 to 10 numeric rating scale, respectively. Worst and average residual limb pain improved 5.4 (3.7) and 3.5 (2.4) points, respectively.Conclusions:These cases suggest that pulsed electromagnetic field therapy may be an effective treatment for intractable postamputation pain. Considering the low patient burden of noninvasive, wearable devices, combined with few contraindications and no significant side effects or adverse events, further study with a randomized, controlled trial is warranted.

The objective was to assess the postsurgical outcomes of regenerative peripheral nerve interface (RPNI) surgery in a prospective cohort of major lower extremity amputation patients with chronic postamputation pain. Chronic pain in lower limb amputation patients is commonly the result of neuroma formation after traumatic peripheral nerve injury. By implanting more proximal transected nerve ends into autologous free muscle grafts, RPNI surgery can treat postamputation pain by diminishing the development of neuromas. RPNI surgery in prior retrospective studies has been shown to mitigate postamputation pain. Twenty-two lower limb amputation patients with established chronic postamputation pain were recruited from 2 studies in this prospective study. All patients underwent RPNI surgery to treat identified symptomatic neuromas within the residual limb. Patient-reported outcome instruments were administered preoperatively and postoperatively at 1 week, 4 months, and 12 months to examine residual limb pain (McGill Pain Questionnaire, PROMIS Pain Intensity, and PROMIS Pain Interference), phantom limb pain (modified PROMIS Pain Intensity and Phantom Limb sensation questionnaire), psychosocial status (PHQ-9, GAD-7, and PCS), and functional (OPUS) outcomes. RPNI surgery significantly improved residual limb pain. While phantom limb sensation improved significantly, phantom limb pain demonstrated a modest decrease. Psychosocial outcomes also improved significantly after RPNI surgery. Prosthetic use slightly increased, and patients did not experience loss of function. RPNI surgery leverages the processes of reinnervation to successfully treat residual limb pain and improve psychosocial outcomes in patients with chronic postamputation pain. Phantom limb pain may be more difficult to treat in chronic pain patients who have central sensitization at the time of surgery.

Objective: To analyse the prevalence of phantom (limb) pain over time and to analyse factors associated with phantom (limb) pain in a prospective cohort of amputees. Design: A multicentre longitudinal study. Patients: One hundred and thirty-four patients scheduled for amputation were included. Methods: Patients filled in questionnaires before amputation, and postal questionnaires six months, 1½ years and 2½ years to a maximum of 3½ years after amputation. Preoperative assessment included patients’ characteristics, date, side and level of, and reason for amputation. The follow-up questionnaires assessed the frequencies of the experienced phantom pain, prosthetic use and walking distance. The occurrence of phantom pain was defined as phantom pain a few times a day or more frequently. Results: Pre- and postoperative questionnaires were available filled in by 85 amputees (33 females and 52 males). The percentage of lower limb amputees with phantom pain was the highest at six months after amputation, and of upper limb amputees at 1½ years. In general, more women than men experienced phantom pain. One and a half years and 2½ years after amputation the highest percentages of the lower limb amputees used their prosthesis more than 4 hours a day (66%), after that time this percentage decreased to 60%. The results of the two-level logistic regression analysis to predict phantom pain show that phantom pain was less frequently present in men (odds ratio (OR) = 0.12), in lower limb amputees (OR = 0.14) and that it decreased in due course (OR = 0.53 for 1 year). Conclusion: Protective factors for phantom pain are: being male, having a lower limb amputation and the time elapsed since amputation.

BackgroundPopulation ageing is associated with an increase in the number of persons with dementia, which constitutes a significant public health issue. The Hong Kong Mental Morbidity Survey for Older People (HKMMSOP) was carried out to evaluate the local prevalence of dementia and the factors that modulated the disease development.MethodParticipants aged 60 or over, stratified with age groups, were recruited through random sampling of residential addresses in Hong Kong. They underwent an assessment of their cognitive function (Montreal Cognitive Assessment, MoCA; Clinical Dementia Rating, CDR), physical health (Cumulative Illness Rating Scale, CIRS) and mental health (Clinical Interview Schedule‐Revised, CIS‐R; Short Warwick‐Edinburgh Mental Wellbeing Scale, SWEMWBS). Associative factors of neurocognitive disorders were determined by multinomial regression, with neurocognitive disorders as dependent variables.ResultIn this interim analysis, 4369 participants of HKMMSOP were included. Their mean age was 69.6, and there was a slight female preponderance (56.3%). On average, they received 8.8 years of education, and their mean MoCA score was 23.8 (SD 4.9). Using CDR, 71.8% were evaluated as having normal cognition, 23.1% with a mild neurocognitive disorder (ND), and 5.2% with a major ND. Older or less educated participants had a higher risk of developing mild and major ND (p<0.001). But the relationships between cognition and physical and mental health differed in the mild and major ND groups. Among those with mild ND, a higher CIRS total score (p<0.001), a higher CIS‐R total score (p<0.001) and a lower SWEMWBS score (p = 0.002) were significantly associated with CDR. However, only CIRS total score (p = 0.004) and SWEMWBS score (p<0.001) remained significant in the major ND group.ConclusionPoorer physical and mental health and lower mental well‐being and life satisfaction were associated with an increased risk of mild ND. But as the disease progressed, lower mental well‐being and life satisfaction and poorer physical health remained significant factors. On the contrary, a higher level of mental symptoms, as exemplified by CIS‐R, was not significantly associated with major ND. It sheds some light on the factors that may modulate the course of the disease and appropriate preventive measures.