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Purpose of Review: Chronic postamputation pain (cPAP) remains a clinical challenge, and current understanding places a high emphasis on prevention strategies. Unfortunately, there is still no evidence-based regimen to reliably prevent chronic pain after amputation., Recent Findings: Risk factors for the development of phantom limb pain have been proposed. Analgesic preventive interventions are numerous and no silver bullet has been found. Novel techniques such as neuromodulation and cryoablation have been proposed. Surgical techniques focusing on reimplantation of the injured nerve might reduce the incidence of phantom limb pain after surgery., Summary: Phantom limb pain is a multifactorial process involving profound functional and structural changes in the peripheral and central nervous system. These changes interact with individual medical, psychosocial and genetic patient risk factors. The patient collective of amputees is very heterogeneous. Available evidence suggests that efforts should focus on prevention of phantom limb pain, since treatment is notoriously difficult. Questions as yet unanswered include the evidence-base of specific analgesic interventions, their optimal "window of opportunity" where they may be most effective, and whether patient stratification according to biopsychosocial risk factors can help guide preventive therapy., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Postamputation phantom pain is notoriously persistent with few validated treatments. Cryoneurolysis involves the application of low temperatures to reversibly ablate peripheral nerves. The authors tested the hypothesis that a single cryoneurolysis treatment would decrease phantom pain 4 months later., Methods: The authors enrolled patients with a lower-limb amputation and established phantom pain. Each received a single-injection femoral and sciatic nerve block with lidocaine and was subsequently randomized to receive either ultrasound-guided percutaneous cryoneurolysis or sham treatment at these same locations. The primary outcome was the change in average phantom pain intensity between baseline and 4 months as measured with a numeric rating scale (0 to 10), after which an optional crossover treatment was offered. Investigators, participants, and clinical staff were masked to treatment group assignment with the exception of the treating physician performing the cryoneurolysis, who had no subsequent participant interaction., Results: Pretreatment phantom pain scores were similar in both groups, with a median [quartiles] of 5.0 [4.0, 6.0] for active treatment and 5.0 [4.0, 7.0] for sham. After 4 months, pain intensity decreased by 0.5 [-0.5, 3.0] in patients given cryoneurolysis (n = 71) versus 0 [0, 3] in patients given sham (n = 73), with an estimated difference (95% CI) of -0.1 (-1.0 to 0.7), P = 0.759. Following their statistical gatekeeping protocol, the authors did not make inferences or draw conclusions on secondary endpoints. One serious adverse event occurred after a protocol deviation in which a femoral nerve cryolesion was induced just below the inguinal ligament-instead of the sensory-only saphenous nerve-which resulted in quadriceps weakness, and possibly a fall and clavicle fracture., Conclusions: Percutaneous cryoneurolysis did not decrease chronic lower extremity phantom limb pain 4 months after treatment. However, these results were based upon the authors' specific study protocol, and since the optimal cryoneurolysis treatment parameters such as freeze duration and anatomic treatment location remain unknown, further research is warranted., (Copyright © 2022, the American Society of Anesthesiologists. All Rights Reserved.)

Background: We recently reported that a 6-day continuous peripheral nerve block reduced established postamputation phantom pain 3 weeks after treatment ended. However, the immediate effects of perineural infusion (secondary outcomes) have yet to be reported., Methods: Participants from 5 enrolling academic centers with an upper or lower limb amputation and established phantom pain received a single-injection ropivacaine peripheral nerve block(s) and perineural catheter insertion(s). They were subsequently randomized to receive a 6-day ambulatory perineural infusion of either ropivacaine 0.5% or normal saline in a double-masked fashion. Participants were contacted by telephone 1, 7, 14, 21, and 28 days after the infusion started, with pain measured using the Numeric Rating Scale. Treatment effects were assessed using the Wilcoxon rank-sum test at each time point. Adjusting for 4 time points (days 1, 7, 14, and 21), P < .0125 was deemed statistically significant. Significance at 28 days was reported using methods from the original, previously published article., Results: Pretreatment average phantom and residual pain scores were balanced between the groups. The day after infusion initiation (day 1), average phantom, and residual limb pain intensity was lower in patients receiving local anesthetic (n = 71) versus placebo (n = 73): median [quartiles] of 0 [0-2.5] vs 3.3 [0-5.0], median difference (98.75% confidence interval [CI]) of -1.0 (-3.0 to 0) for phantom pain (P = .001) and 0 [0-0] vs 0 [0-4.3], and median difference 0.0 (-2.0 to 0.0) for residual limb pain (P < .001). Pain's interference with physical and emotional functioning as measured with the interference domain of the Brief Pain Inventory improved during the infusion on day 1 for patients receiving local anesthetic versus placebo: 0 [0-10] vs 10 [0-40], median difference (98.75% CI) of 0.0 (-16.0 to 0.0), P = .002. Following infusion discontinuation (day 6), a few differences were found between the active and placebo treatment groups between days 7 and 21. In general, sample medians for average phantom and residual limb pain scores gradually increased after catheter removal for both treatments, but to a greater degree in the control group until day 28, at which time the differences between the groups returned to statistical significance., Conclusions: This secondary analysis suggests that a continuous peripheral nerve block decreases phantom and residual limb pain during the infusion, although few improvements were again detected until day 28, 3 weeks following catheter removal., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2021 International Anesthesia Research Society.)

Abstract: A 36-yr-old man with a history of industrial accident causing traumatic left hip disarticulation, pubic symphysis, and right sacroiliac joint fractures presented with a 3-yr history of left-sided lower back pain radiating down the amputated limb. Computed tomography lumbar spine showed osteophytes surrounding the sacroiliac joint bilaterally with reduced left L4-L5 foraminal space. A fluoroscopically guided left sacroiliac steroid injection led to mild improvement in low back pain. Magnetic resonance imaging of the lumbar spine without contrast showed transitional type L5 vertebral body with left-sided flowing osteophytes abutting the extraforaminal L4 and L5 nerves. Ultimately, multilevel left fluoroscopically guided transforaminal epidural steroid injection at L4-L5 and L5-S1 significantly improved symptoms. Although phantom radiculopathy is a rare entity, clinical suspicion of degenerative spine disease or other pathology contributing to nerve impingement in patients with amputations should remain; this unique case discusses bony osteophyte complex as the cause for phantom radiculopathy instead of previously described disc herniation. Magnetic resonance imaging remains a key tool in delineating causes of low back pain among patients with lower limb amputations., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Phantom limb pain is thought to be sustained by reentrant neural pathways, which provoke dysfunctional reorganization in the somatosensory cortex. We hypothesized that disrupting reentrant pathways with a 6-day-long continuous peripheral nerve block reduces phantom pain 4 weeks after treatment. We enrolled patients who had an upper- or lower-limb amputation and established phantom pain. Each was randomized to receive a 6-day perineural infusion of either ropivacaine or normal saline. The primary outcome was the average phantom pain severity as measured with a Numeric Rating Scale (0-10) at 4 weeks, after which an optional crossover treatment was offered within the following 0 to 12 weeks. Pretreatment pain scores were similar in both groups, with a median (interquartile range) of 5.0 (4.0, 7.0) for each. After 4 weeks, average phantom limb pain intensity was a mean (SD) of 3.0 (2.9) in patients given local anesthetic vs 4.5 (2.6) in those given placebo (difference [95% confidence interval] 1.3 [0.4, 2.2], P = 0.003). Patients given local anesthetic had improved global impression of change and less pain-induced physical and emotional dysfunction, but did not differ on depression scores. For subjects who received only the first infusion (no self-selected crossover), the median decrease in phantom limb pain at 6 months for treated subjects was 3.0 (0, 5.0) vs 1.5 (0, 5.0) for the placebo group; there seemed to be little residual benefit at 12 months. We conclude that a 6-day continuous peripheral nerve block reduces phantom limb pain as well as physical and emotional dysfunction for at least 1 month., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

In this randomized, double-blind, placebo-controlled crossover study, we investigated whether a peripheral nerve block could temporarily eliminate phantom and stump pain after amputation. Amputees with constant postamputation pain were included and randomized to receive a nerve block with lidocaine 2% with adrenaline or saline in a crossover design. Spontaneous phantom and stump pain and evoked responses were assessed at baseline and at fixed time-points until 120 minutes after lidocaine or saline injection. The primary outcome was the difference in absolute change between worst pain intensity, either phantom or stump pain, at baseline and at 30 minutes after lidocaine or saline injection. Twelve amputees were randomized and 9 patients were included in the analysis. The absolute change in median worst pain intensity between lidocaine and saline injection was -2.0 (interquartile range, -4.0 to 0.0) (n = 9, P = 0.12). Nine of 9 patients reported at least some pain relief after lidocaine injection compared with only 2 of 9 patients after saline injection (P = 0.02). Phantom pain intensity was significantly reduced after lidocaine compared with saline injection (P = 0.04), whereas there was no significant change in stump pain intensity between the 2 interventions (P = 0.17). In all 9 amputees, evoked responses were eliminated after lidocaine injection. Thus, our findings suggest that afferent input from the peripheral nervous system plays an important role in postamputation pain.

Nearly all amputees continue to feel their missing limb as if it still existed, and many experience chronic phantom limb pain (PLP). What is the origin of these sensations? There is currently a broad consensus among investigators that PLP is a top-down phenomenon, triggered by loss of sensory input and caused by maladaptive cortical plasticity. We tested the alternative hypothesis that PLP is primarily a bottom-up process, due not to the loss of input but rather to exaggerated input, generated ectopically in axotomized primary afferent neurons in the dorsal root ganglia (DRGs) that used to innervate the limb. In 31 amputees, the local anesthetic lidocaine was applied intrathecally and/or to the DRG surface (intraforaminal epidural block). This rapidly and reversibly extinguished PLP and also nonpainful phantom limb sensation (npPLS). Control injections were ineffective. For intraforaminal block, the effect was topographically appropriate. The suppression of PLP and npPLS could also be demonstrated using dilute lidocaine concentrations that are sufficient to suppress DRG ectopia but not to block the propagation of impulses generated further distally in the nerve. PLP is driven primarily by activity generated within the DRG. We recommend the DRG as a target for treatment of PLP and perhaps also other types of regional neuropathic pain., (Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Introduction: Managing neuropathic pain can be very challenging, with standard medical therapies often providing inadequate relief. It has recently been reported in the literature that statins alleviate neuropathic pain in the rat model. We present a case report in which an above-the-knee amputee achieved relief of his neuropathic stump pain with atorvastatin., Case Report: We describe the case of a 50-year-old man with a 12-year history of chronic neuropathic stump pain and sporadic phantom limb pain following an above-the-knee amputation. For 11 years the pain was managed with gabapentin 300 mg 3 times daily plus oxycodone 10 mg twice daily. He autonomously weaned himself to gabapentin 300 mg once daily and oxycodone 10 mg once daily, exacerbating his stump pain in the process. After starting atorvastatin 20 mg once daily for hypercholesterolemia, he immediately experienced decreased intensity of his stump pain, but his phantom pain persisted at its usual intensity., Conclusions: More studies are needed to characterize the analgesic effects of statins better. In patients who have neuropathic pain refractory to traditional treatment options or, rather, decline traditional treatment options, statin therapy may be helpful.

Objective: Botulinum toxin type A (Botox) injection has been used to manage pain. However, it remains to be proved whether Botox injection is effective to relieve residual limb pain (RLP) and phantom limb pain (PLP)., Design: Randomized, double-blinded pilot study., Setting: Medical College and an outpatient clinic in Department of Physical Medicine and Rehabilitation., Participants: Amputees (n=14) with intractable RLP and/or PLP who failed in the conventional treatments., Interventions: Study amputees were randomized to receive 1 Botox injection versus the combination of Lidocaine and Depomedrol injection. Each patient was evaluated at baseline and every month after the injection for 6 months., Main Outcome Measure: The changes of RLP and PLP as recorded by VAS, and the changes of the pressure pain tolerance as determined by a pressure algometer., Results: All patients completed the protocol treatment without acute side effects, and monthly assessments of RLP, PLP, and pain tolerance after the treatment. The time trend in the outcomes was modeled as an immediate change owing to the treatment followed by a linear tread afterward. Repeated measures were incorporated using mixed effects modeling. We found that both Botox and Lidocaine/Depomedrol injections resulted in immediate improvements of RLP (Botox: P=0.002; Lidocaine/Depomedrol: P=0.06) and pain tolerance (Botox: P=0.01; Lidocaine/Depomedrol: P=0.07). The treatment effect lasted for 6 months in both groups. The patients who received Botox injection had higher starting pain than those who received Lidocaine/Depomedrol injection (P=0.07). However, there were no statistical differences in RLP and pain tolerance between these 2 groups. In addition, no improvement of PLP was observed after Botox or Lidocaine/Depomedrol injection., Conclusions: Both Botox and Lidocaine/Depomedrol injections resulted in immediate improvement of RLP (not PLP) and pain tolerance, which lasted for 6 months in amputees who failed in conventional treatments.

Purpose of Review: Phantom pain is a frequent consequence of amputation or deafferentation. There are many possible contributing mechanisms, including stump-related pathology, spinal and cortical changes. Phantom limb pain is notoriously difficult to treat. Continued consideration of the factors associated with phantom pain and its treatment is of utmost importance, not only to advance the scientific knowledge about the experience of the body and neuropathic pain, but also fundamentally to promote efficacious pain management., Recent Findings: This review first discusses the mechanisms associated with phantom pain and summarizes the current treatments. The mechanisms underlying phantom pain primarily relate to peripheral/spinal dysfunction, and supraspinal and central plasticity in sensorimotor body representations. The most promising methods for managing phantom pain address the maladaptive changes at multiple levels of the neuraxis, for example, complementing pharmacological administration with physical, psychological or behavioural intervention. These supplementary techniques are even efficacious in isolation, perhaps by replacing the absent afferent signals from the amputated limb, thereby restoring disrupted bodily representations., Summary: Ultimately, for optimal patient outcomes, treatments should be both symptom and mechanism targeted.

Background: Severe preamputation pain is associated with phantom limb pain (PLP) development in limb amputees. We investigated whether optimized perioperative analgesia reduces PLP at 6-month follow-up., Methods: A total of 65 patients underwent lower-limb amputation and were assigned to five analgesic regimens: (1) Epi/Epi/Epi patients received perioperative epidural analgesia and epidural anesthesia; (2) PCA/Epi/Epi patients received preoperative intravenous patient-controlled analgesia (PCA), postoperative epidural analgesia, and epidural anesthesia; (3) PCA/Epi/PCA patients received perioperative intravenous PCA and epidural anesthesia; (4) PCA/GA/PCA patients received perioperative intravenous PCA and general anesthesia (GA); (5) controls received conventional analgesia and GA. Epidural analgesia or intravenous PCA started 48 h preoperatively and continued 48 h postoperatively. The results of the visual analog scale and the McGill Pain Questionnaire were recorded perioperatively and at 1 and 6 months., Results: At 6 months, median (minimum-maximum) PLP and P values (intervention groups vs. control group) for the visual analog scale were as follows: 0 (0-20) for Epi/Epi/Epi (P = 0.001), 0 (0-42) for PCA/Epi/Epi (P = 0.014), 20 (0-40) for PCA/Epi/PCA (P = 0.532), 0 (0-30) for PCA/GA/PCA (P = 0.008), and 20 (0-58) for controls. The values for the McGill Pain Questionnaire were as follows: 0 (0-7) for Epi/Epi/Epi (P < 0.001), 0 (0-9) for PCA/Epi/Epi (P = 0.003), 6 (0-11) for PCA/Epi/PCA (P = 0.208), 0 (0-9) for PCA/GA/PCA (P = 0.003), and 7 (0-15) for controls. At 6 months, PLP was present in 1 of 13 Epi/Epi/Epi, 4 of 13 PCA/Epi/Epi, and 3 of 13 PCA/GA/PCA patients versus 9 of 12 control patients (P = 0.001, P = 0.027, and P = 0.009, respectively). Residual limb pain at 6 months was insignificant., Conclusions: Optimized epidural analgesia or intravenous PCA, starting 48 h preoperatively and continuing for 48 h postoperatively, decreases PLP at 6 months.

We present the cases of two patients who suffered severe lower extremity injuries and subsequently developed phantom limb pain (PLP) that was refractory to high dose opioids and adjunctive pain medications. Both patients were receiving large doses of oral methadone, IV hydromorphone via a patient-controlled analgesia delivery system, and adjunctive medications including tricyclic antidepressants, nonsteroidal anti-inflammatory medications, and anti-epileptics. Despite these treatments, the patients had severe PLP. Upon induction of the oral N-methyl-D-aspartate receptor antagonist memantine, both patients had a profound reduction in their PLP without any apparent side effects from the medication.

Background: Stump and phantom pains are debilitating sequelae of amputations that are often resistant to treatment. The efficacy of pharmacologic therapies, including opioids and sodium channel blockers, for postamputation pain is uncertain., Methods: The authors conducted a double-blind, randomized, placebo-controlled, crossover study in adult patients with postamputation pain of 6 months or longer and greater than 3 on a 0-10 numeric pain rating scale. Each of the three treatment periods (morphine, mexiletine, or placebo) included a 1-week drug-free interval followed by 4-week titration, 2-week maintenance, and 2-week drug-taper phases. The primary outcome measure was change in average pain intensity from the drug-free baseline to the last week of maintenance., Results: Sixty amputees were enrolled; data were analyzed from 56 subjects for one drug period, 45 subjects for two drug periods, and 35 subjects who completed all three drug periods. The mean morphine and mexiletine dosages were 112 and 933 mg, respectively. Morphine treatment provided lower pain scores compared with placebo and mexiletine (P = 0.0003). The mean percent pain relief during treatment with placebo, mexiletine, and morphine was 19, 30, and 53%, respectively (P < 0.0001, morphine vs. placebo and mexiletine). The numbers needed to treat to obtain 50% and 33% decreases in pain intensity with morphine were 5.6 and 4.5, respectively. Treatment with morphine was associated with a higher rate of side effects., Conclusions: Therapy with morphine, but not mexiletine, resulted in a decrease in intensity of postamputation pain but was associated with a higher rate of side effects and no improvement in self-reported levels of overall functional activity and pain-related interference in daily activities.

Persistent pain has been reported in up to 80% of patients after limb amputation. The mechanisms are not fully understood, but nerve injury during amputation is important, with evidence for the crucial involvement of the spinal N-methyl d-aspartate (NMDA) receptor in central changes. The study objective was to assess the effect of pre-emptively modulating sensory input with epidural ketamine (an NMDA antagonist) on post-amputation pain and sensory processing. The study recruited 53 patients undergoing lower limb amputation who received a combined intrathecal/epidural anaesthetic for surgery followed by a randomised epidural infusion (Group K received racemic ketamine and bupivacaine; Group S received saline and bupivacaine). Neither general anaesthesia nor opioids were used during the peri-operative period. Pain characteristics were assessed for 12 months. The primary endpoint was incidence and severity of post-amputation pain. Persistent pain at one year was much less in both groups than in comparable studies, with no significant difference between groups (Group K=21% (3/14) and 50% (7/14); and Group S=33% (5/15) and 40% (6/15) for stump and phantom pain, respectively). Post-operative analgesia was significantly better in Group K, with reduced stump sensitivity. The intrathecal/epidural technique used, with peri-operative sensory attenuation, may have reduced ongoing sensitisation, reducing the overall incidence of persistent pain. The improved short-term analgesia and reduced mechanical sensitivity in Group K may reflect acute effects of ketamine on central sensitisation. Longer term effects on mood were detected in Group K that requires further study.

Background: The inflammatory cytokine tumor necrosis factor-alpha has been shown to play a pivotal role in the development and maintenance of a wide variety of neuropathic pain conditions. Not surprisingly, systemic treatment with drugs that block tumor necrosis factor have been demonstrated to alleviate pain and pain-related behaviors in clinical and preclinical studies, respectively. Despite evidence that local administration of this drug class may be more efficacious than systemic administration, there are no clinical studies to support or refute this assertion., Objective: To report results on the use of perineural etanercept in 6 traumatic amputees with postamputation pain., Methods: The authors treated 6 soldiers with residual limb and phantom pain with a series of perineural etanercept injections., Results: Five of the six patients reported significant improvements in residual limb pain at rest and with activity, phantom limb pain, functional capacity, and psychologic well-being 3 months after injections. The one soldier who failed therapy was the only patient who presented with pain greater than 1 year in duration. At the reduced doses administered, no adverse effects were observed., Discussion: These findings support preclinical evidence that the local administration of tumor necrosis factor inhibitors may prove to be a safe and effective treatment for challenging pain conditions.

Background: Pain after amputation is common but difficult to treat. Therefore, the authors examined whether postoperative treatment with gabapentin could reduce postamputation stump and phantom pain., Methods: Forty-six patients scheduled to undergo lower limb amputation were randomly assigned to receive oral gabapentin or placebo. Treatment was started on the first postoperative day and continued for 30 days. The daily dose of gabapentin or placebo was gradually increased to 2,400 mg/day. The intensity of stump and phantom pain was recorded every day on a numeric rating scale (0-10) during the 30-day treatment period. Five interviews were performed after 7, 14, and 30 days and after 3 and 6 months., Results: Results from 41 patients were included in the data analysis. The risk of phantom pain (gabapentin vs. placebo) was 55.0% versus 52.6% (risk difference, 2.4%; 95% confidence interval, -28.9 to 33.7%; P = 0.88; 30 days) and 58.8% versus 50.0% (risk difference, 8.8%; 95% confidence interval, -23.3 to 40.9%; P = 0.59; 6 months). The median intensity of phantom pain (gabapentin vs. placebo) was 1.5 (range, 0-9.0) versus 1.2 (range, 0-6.6) (P = 0.60; 30 days) and 1.0 (range, 0-6.0) versus 0.5 (range, 0-5.0) (P = 0.77; 6 months). The median intensity of stump pain was 0.85 (range, 0-8.2) versus 1.0 (range, 0-5.4) (P = 0.68; 30 days) and 0 (range, 0-8.0) versus 0 (range, 0-5.0) (P = 0.58; 6 months)., Conclusion: Gabapentin administered in the first 30 postoperative days after amputation does not reduce the incidence or intensity of postamputation pain.

Background: Pain after amputation is common but difficult to treat, and few controlled treatment studies exist., Methods: In the current study, 94 treatment-naive posttraumatic limb amputees with phantom pain (intensity: mean visual analog scale score [0-100], 40 [95% confidence interval, 38-41]) were randomly assigned to receive individually titrated doses of tramadol, placebo (double-blind comparison), or amitriptyline (open comparison) for 1 month. Nonresponders were crossed over to the alternative active treatment., Results: After 1 month, phantom pain intensity was 1 (0-2) in the 48 tramadol responders (mean dose, 448 mg [95% confidence interval, 391-505 mg]), 0 (0-0) in the 40 amitriptyline responders (55 [50-59] mg), and 0 (0-0) in the 2 placebo responders, with similar effects on stump pain. Cytochrome P-450 2D6 slow metabolizers derived greater analgesia from tramadol and less from amitriptyline compared with fast metabolizers in the first treatment week (P < 0.01). Electrical pain thresholds increased and pain during suprathreshold stimulation decreased markedly on the stump and, to a lesser extent, on the contralateral limb after 1 month of treatment with amitriptyline or tramadol. Adverse effects were minor in all groups, but more common with tramadol., Conclusions: In treatment-naive patients, both amitriptyline and tramadol provided excellent and stable phantom limb and stump pain control with no major adverse events. Both drugs demonstrated consistent and large antinociceptive effects on both the stump and the intact limbs.

Patients who had previously undergone amputation of the arm (n = 2) or leg (n = 2) were treated with botulinum toxin type B injections at several trigger points of their stump musculature. We administered a total dose of 2500 IU of botulinum toxin type B (Neurobloc, Elan Pharma, Munich, Germany) to the arm amputation stumps, 5000 IU for one amputation of the lower leg, and 2500 IU to the other lower leg amputation of a patient with a very low baseline body weight. Two patients reported that the injection was very painful. All patients experienced a reduction in stump pain, which lasted for many weeks. Other reports included a reduction in the frequency of pain attacks, cessation of "balloon feelings," improvement in stump allodynia, and decreased occurrence of involuntary stump movements. In addition, quality of sleep at night significantly improved in one patient. Botulinum toxin type B can therefore be regarded as a new treatment option for possible improvements in the rehabilitation of amputees.

We describe a 78-year-old gentleman who, following bilateral above-knee amputations, developed symptoms of restless legs syndrome in the absent portions of his lower extremities. These symptoms improved with dopamine agonist therapy. In addition, he later developed parkinsonism with prominent rest tremor on metoclopramide. This suggests that this individual had a dopamine-deficient state which predisposed him to both restless legs syndrome and drug-induced or drug-exacerbated parkinsonism. We propose expanding the spectrum of phantom limb phenomena to include phantom restless legs.

Unlabelled: In the present study we investigated the effect of the N-methyl-D-aspartic acid (NMDA) receptor antagonist memantine (30 mg/d) on the intensity of chronic phantom limb pain (PLP) and cortical reorganization. In 8 patients with chronic PLP, memantine was tested in a placebo-controlled double-blinded crossover trial of 4 wk duration per trial. The intensity of PLP was rated hourly by the patients on a visual analog scale during baseline and both treatment periods. At the same time points, the functional organization of the primary somatosensory cortex (SI) was determined by neuromagnetic source imaging. In comparison to baseline and placebo, the NMDA receptor antagonist had no effect on the intensity of chronic PLP. In none of the periods were significant changes in the functional organization of SI observed. Although the conclusions regarding the clinical effect are limited because of the small sample size, the data indicate that in the studied dosage the NMDA receptor antagonist memantine is ineffective in the treatment of chronic PLP and is also ineffective for the reduction of associated neural plasticity in the primary SI., Implications: NMDA receptors play a substantial role in central nervous system changes underlying neuropathic pain. In a placebo-controlled double-blinded study we tested the effect of 30 mg memantine on chronic phantom limb pain and pain-associated cortical reorganization.

Phantom limb pain (PLP) associated neuroplastic changes are partly mediated by excitatory amino acids at NMDA receptor sites. This study was undertaken to deduce if NMDA-receptor antagonists may be effective in patients with chronic PLP. Therefore a four week double-blinded, randomized placebo-controlled trial was performed to evaluate the efficacy of 30 mg memantine/day, an orally administrable NMDA receptor antagonist.Thirty-six patients, 18 per group, with a history of at least 12 months PLP and an average pain of at least 4 on the 11-point numeric rating scale (NRS) were enrolled. The patients completed a standardized questionnaire before the trial. PLP intensity and the level of eight complaints were assessed during the trial. Number needed to treat (NNT) was calculated based on the average PLP during the 3rd week (steady state). In both groups, PLP declined significantly in comparison with the baseline (verum: 5.1 (+/-2.1) to 3,8 (+/-2,3), placebo from 5.1 (+/-2.0) to 3.2 (+/-1,46) NRS) without a re-rising of the PLP during the washout period. Mean pain relief was 47% in the memantine group (10 patients reported more than 50% relief), 40% in the placebo group (6>50%): NNT were 4.5 (KI: 2.1-10.6). Analysis of covariance demonstrated a significant impact only on the prior PLP intensity, but no treatment effect. Two patients have demonstrated long-term pain relief under memantine until now (16 months). The total number of slight adverse events were comparable in both groups, but the overall number of severe events was higher in the memantine group (P<0.05). This trial failed to demonstrate a significant clinical benefit of the NMDA-receptor antagonist memantine in chronic PLP. The administration of a higher dosage is probably not tolerable.

Background: Phantom limb pain is an intriguing pain syndrome that may result from damage to peripheral nerve tissue but could also involve central amplifying congeners. N-methyl-D-aspartate (NMDA)-receptor antagonists were recently shown to alleviate neuropathic pain in both animal and human models. Dextromethorphan is a noncompetitive NMDA-receptor antagonist., Study Design: Oral dextromethorphan (120-180 mg daily) was administered to three selected cancer patients during a 3-week study and an additional 1 month of treatment with the dosage subjectively judged to be best., Results: Oral dextromethorphan effectively reduced postamputation phantom limb pain, bestowing improvement in feeling and minimizing sedation in comparison with the pretreatment or placebo conditions, with no side effects. Pain recurred in one patient 1 month after treatment was stopped., Conclusions: Further clinical trials are warranted to determine the optimal dosage and identify which patients with phantom pain would benefit the most from this therapeutic approach.

Objective: The objective of this case series was to determine if severe phantom limb pain could be reduced with oral methadone., Design: Four cases of phantom limb pain refractory to multiple treatment modalities were treated with oral methadone., Setting: Pain clinic at a major university medical center., Patients: Four patients with severe, intractable phantom limb pain., Intervention: Oral methadone was administered, starting with a low dose of 2 to 5 mg twice a day or three times a day and slowly titrated upward to achieve pain relief., Outcome Measures: Repeated administration of a visual analog scale for pain., Results and Conclusions: Administration of oral methadone may be of value in the treatment of phantom limb pain; controlled clinical trials would be appropriate to verify this observation.

Background: Phantom and stump pains, common sequelae of limb amputations, are significant impediments to rehabilitation of amputees. The pathophysiology and optimal treatment of postamputation pain states are unclear. While stump pain may result from neuromas in the stump, phantom pain is thought to be related to cortical reorganization. The authors hypothesized that morphine and lidocaine may have differential effectiveness on stump and phantom pains., Methods: The authors conducted a randomized double-blind, active-placebo-controlled, crossover trial to compare the analgesic effects of intravenous morphine and lidocaine on postamputation stump and phantom pains. An intravenous bolus followed by an intravenous infusion of morphine (0.05 mg/kg bolus + 0.2 mg/kg infusion over 40 min), lidocaine (1 mg/kg bolus + 4 mg/kg infusion) and the active placebo, diphenhydramine (10 mg bolus + 40 mg infusion), were performed on three consecutive days. Phantom and stump pain ratings and sedation scores were recorded at 5-min intervals using a 0-100 visual analog scale. Pain measures were initiated 30 min before drug infusion and continued until 30 min after the end of infusion. Subjects' self-reported pain relief and satisfaction were assessed at the end of each infusion., Results: Thirty-one of 32 subjects enrolled completed the study. Eleven subjects had both stump and phantom pains, 11 and 9 subjects had stump and phantom pain alone, respectively. Baseline pain scores were similar in the three drug groups. Compared with placebo, morphine reduced both stump and phantom pains significantly (P < 0.01). In contrast, lidocaine decreased stump (P < 0.01), but not phantom pain. The changes in sedation scores for morphine and lidocaine were not significantly different from placebo. Compared with placebo, self-reported stump pain relief was significantly greater for lidocaine (P < 0.05) and morphine (P < 0.01), while phantom pain relief was greater only for morphine (P < 0.01). Satisfaction scores were significantly higher for lidocaine (mean +/- SD: 39.3 +/- 37.8, P < 0.01) and morphine (45.9 +/- 35.5, P < 0.01) when compared with placebo (9.6 +/- 21.0)., Conclusions: Stump pain was diminished both by morphine and lidocaine, while phantom pain was diminished only by morphine, suggesting that the mechanisms and pharmacological sensitivity of stump and phantom pains are different.

The efficacy of oral retarded morphine sulphate (MST) was tested against placebo in a double-blind crossover design in 12 patients with phantom limb pain after unilateral leg or arm amputation. Two counterbalanced treatment phases of 4 weeks each were initiated with an intravenous test infusion of MST or Placebo. The titration phase was 2 weeks. The dose of MST was titrated to at least 70 mg/day and at highest 300 mg/day. Pain intensity was assessed hourly on visual analog scales during a 4-week treatment-free phase, both treatment phases and at two follow-ups (6 and 12 months). Reorganization of somatosensory cortex, electric perception and pain thresholds as well as selective attention were measured pre- and post-treatment. A significant pain reduction was found during MST but not during placebo. A clinically relevant response to MST (pain reduction of more than 50%) was evident in 42%, a partial response (pain reduction of 25-50%) in 8% of the patients. Neuromagnetic source imaging of three patients showed initial evidence for reduced cortical reorganization under MST concurrent with the reduction in pain intensity. Perception and pain thresholds were not significantly altered whereas attention was significantly lower under MST. Thus, opioids show efficacy in the treatment of phantom limb pain and may potentially influence also cortical reorganization. These data need to be replicated in larger patient samples.

This paper describes studies on plasticity that the author undertook with Patrick Wall in the mid '70s, and then reviews recent related studies in humans carried out in the author's laboratory. The human studies have shown that thalamic neurons frequently have subliminal receptive fields (RFs) and immediately following a reversible block of afferent activity from the RF some neurons develop increased sensitivity to tactile stimulation at sites outside their normal RF. Also described and discussed are novel findings in patients that had a limb amputated. The results suggested an expansion of the representation of the proximal limb into the thalamic region that used to represent the amputated part. Furthermore, in those patients that had a phantom limb, microstimulation in this region induced sensations perceived as originating on the phantom.

A 39-year-old patient developed phantom pain after amputation of both upper arms following a burn injury. The pain did not respond to naproxen, morphine, carbamazepine, amitriptyline, calcitonin or transcutaneous electrical nerve stimulation (TENS). At the 39th post-operative day an axillary catheter was placed on the right side, as well as an interscalene catheter on the left. Ropivacaine 0.2% was infused, starting with a rate of 4 ml/h, that was increased to 6 ml/h during the subsequent 6 days. Within 20 min of catheter placement complete pain relief was achieved. The patient did not need any other analgesics and remained painfree for 7 months. Neither motor block, nor any other side effects occurred during the infusion of ropivacaine 0.2%. Thus, the patient not only received analgesia, but also got an effective treatment of established phantom pain. A similar approach with bupivacaine may not have been feasible, because of the possibility of toxic side effects. Ropivacaine is a long-acting local anaesthetic which is less toxic than bupivacaine and has the additional advantage of producing less motor-blockade in the concentration used, so the patient was able to move actively without experiencing any pain.

Objective: To examine whether the oral administration of barbiturates is of clinical use in a patient with central pain., Setting: Pain Clinic, Osaka University Medical Hospital, Osaka, Japan., Patient: A patient with central pain after loss of his left upper extremity., Interventions: A 50-mg dose of intravenous amobarbital, which produced a plasma concentration of 2.5-4.0 microg/ml, was effective in reducing the central pain. Subsequently, doses of 300-400 mg/day were administered orally; these succeeded in achieving similar plasma concentration levels., Results and Conclusions: Oral administration of barbiturate did not alleviate central pain, even when the plasma concentration was the same as the effective level in intravenous use. Pharmacokinetic and pharmacodynamic factors more complex than simple plasma concentrations may be involved in producing the difference in the effects.

Objective: The objective was to assess the analgesic, antihyperesthesic, and anti-allodynic properties of SNX-111 in neuropathic pain., Design: We describe a patient with refractory, severe deafferentation pain successfully treated with SNX-111 in an open-label, baseline-controlled Phase I/II trial., Setting: The patient was hospitalized for treatment and observation., Patient: The patient was a 43-year-old man with intractable deafferentation pain of 23 years' duration secondary to brachial plexus avulsion., Intervention: SNX-111, the first neuron-specific, N-type, voltage-sensitive calcium channel blocker developed for clinical use, was administered by continuous, constant-rate, intrathecal infusion via an indwelling cervical catheter., Outcome Measures: The primary outcome measures were the Visual Analog Scales of Pain Intensity (VASPI) and Pain Relief (VASPR)., Results: The patient experienced complete pain relief (VASPI = 0.0 cm and VASPR = 10.0 cm) with elimination of hyperesthesia and allodynia., Conclusions: SNX-111, administered intrathecally by continuous, constant-rate infusion, produced dose-dependent pain relief in a 43-year-old male patient with a 23-year history of intractable deafferentation and phantom limb pain secondary to brachial plexus avulsion and subsequent amputation. Dizziness, blurred vision, and lateral-gaze nystagmus were dose-dependent side effects that resolved with decreasing dose levels. Complete pain relief was achieved in this patient without side effects after dose adjustment. We conclude that SNX-111 is a potent analgesic, antihyperesthesic, and antiallodynic agent. Controlled studies of SNX-111 in patients with malignant and nonmalignant pain syndromes are warranted and are under way.

Hyperactivity of N-methyl D-aspartate (NMDA) receptors may be one of the factors in the maintenance of persistent stump and phantom limb pain. Ketamine (bolus at 0.1 mg/kg/5 min followed by an infusion of 7 micrograms/kg/min) was administered intravenously to 11 patients with established stump and phantom limb pain in a double-blind saline-controlled study. All 11 patients responded with a decrease in the rating of stump and phantom limb pain assessed by visual analogue scale (VAS) and McGill Pain Questionnaire (MPQ). Ketamine increased pressure-pain thresholds significantly. Wind-up like pain (pain evoked by repeatedly tapping the dysaesthetic skin area) was reduced significantly by ketamine. In contrast, no effect was seen on pain evoked by repeated thermal stimuli. Side effects were observed in nine patients. The results support the notion that stump and phantom pain are generated by activity in afferent fibres activated by mechanical but not by thermal stimuli and that the NMDA receptor is involved in the maintenance of postamputation pain states. NMDA receptor antagonists may have a potential in the treatment of stump and phantom limb pain.

The successful treatment of severe left lower limb phantom pain is reported. Hypnosis and antidepressant drugs were the basis for the treatment which controlled the phantom limb pain and an associated post-traumatic stress disorder.

Objective: To propose clonazepam for use in the empiric treatment of shooting/shocking phantom limb pain., Setting: Outpatient pain clinic associated with a university hospital., Patients: Two patients with phantom limb pain after total hip disarticulation., Interventions: Treatment with clonazepam., Results and Conclusions: Clonazepam provided effective relief for > 6 months in two patients with shooting/shocking phantom limb pain. Although clonazepam therapy is not new, it appears to have been omitted from current pain texts and journals as a treatment option for phantom limb pain.

Three cases are described in which phantom limb pain was successfully treated with ketamine hydrochloride. Possible mechanisms for this observation are suggested.

Salmon calcitonin (s-CT) has been shown to be a valuable analgesic in phantom limb pain (PLP) in several case reports. To evaluate these findings a double-blind crossover comparison of s-CT treatment versus placebo was initiated. Twenty-one out of 161 patients who had undergone major amputations and developed severe PLP 0-7 days after surgery were included in the study. For each patient a matched pair of infusions was prepared containing either 200 IU of s-CT or placebo. Group I (n = 11) was first given s-CT and group II (n = 10) placebo. When PLP reached a level of more than 3 on a numeric analogue scale (NAS) the first infusion was administered. The second infusion (crossover) or more infusions were given when the pain level again exceeded more than 3 on NAS. Using s-CT infusion, PLP was eased from a median of 7 to 4 on NAS in both groups (P less than 0.001), regardless of whether s-CT or placebo was given first. Placebo, however, did not change pain scores (median 7 on NAS, P greater than 0.1). In the s-CT group, but not in the placebo group, 4 individuals remained pain free without a second infusion. Any further treatment was performed with s-CT. One week after the first PLP treatment 19 patients (90%) had pain relief of more than 50%, 16 (76%) were completely pain free, and 15 (71%) never experienced PLP again. One year later 8 out of the 13 surviving patients (62%) still had more than 75% PLP relief. After 2 years PLP exceeded 3 on NAS in 5 individuals (42%), and the remaining 12 patients presented the same PLP as after 1 year. In conclusion, s-CT is a valuable treatment for PLP in the early postoperative period.

Eight patients with established lower limb postamputation stump pain were given lumbar intrathecal fentanyl 25 micrograms and lidocaine 70 mg 2 weeks apart in an attempt to better understand the role of peripheral and central mechanisms in this condition. Baseline pain was recorded and then analgetic and side effects and their duration were assessed. Three self-administered questionnaires with appropriate psychometric proprieties were given to the patients. Intrathecal fentanyl always abolished the pain. Its onset was rapid being heralded within 1-2.5 min by a pleasant sensation of warmth involving the lower trunk and legs. Analgesia was complete by 5-10 min and had a median duration of 8 h. The patients had a sense of well being and were unable to elicit discomfort by pain aggravating maneuvers. Normal motor and sensory functions were retained. Pruritus was the only adverse effect unique to intrathecal fentanyl. Intrathecal lidocaine usually relieved the discomfort but was unable to abolish it in 3 of 8 patients despite adequate neural blockade. Its onset of action was slower and duration of effect shorter than fentanyl. Intrathecal fentanyl provided profound analgesia associated with normalization of stump sensations and euphoria, probably due to a segmental spinal action. The effects of lidocaine were inferior to fentanyl due to the associated motor and sensory paralyses as well as the absence of euphoria. This study suggests that, while peripheral mechanisms played a role, central mechanisms involving the spinal cord were more important in the modulation of established stump pain in the 8 subjects evaluated.

Many treatments have been recommended in the management of phantom limb pain. These have not met with widespread enthusiasm. A new therapeutic endeavour utilizes the group of beta sympathetic blocking drugs. Three case histories of patients with phantom limb pain treated with both beta 1-specific and non-specific beta blocking drugs are reported.

We applied calcitonin in a single-shot treatment to 10 patients with persistent or acute phantom limb pain. Nine patients responded immediately and noted a clear analgesic effect. In contrast a group of non-phantom pain patients of heterogeneous composition did not respond at all, except 1 patient with chronic stump pain. We believe that this could be an exciting new approach to the treatment of phantom limb pain.

In view of several case reports of relief of various neuralgias by propranolo, a double-blind cross-over trial using this drug was conducted in 10 patients with severe persistent pain and paraesthesiae following upper limb peripheral nerve injuries. The patients received up to 240 mg of propranolol per day. Only one patient reported pain relief, but this patient withdrew from the trial. An open trial of propranolol was conducted in 6 other patients with a variety of peripheral nerve lesions. Of these, neuroma tenderness was transiently reduced in one patient and the hyperaesthesia of a painful scar was relieved in another. Routine use of propranolol in such patients cannot be recommended.

Two patients with postamputation stump and phantom limb pain respectively responded favorably to intrathecal fentanyl which temporarily abolished the pain, normalized sensations and produced euphoria without supraspinal effects. One of the patients subsequently received intrathecal, extradural and intravenous fentanyl as well as intrathecal lidocaine. The neuraxial (intrathecal and epidural) fentanyl temporarily abolished the pain. Intravenous fentanyl and intrathecal lidocine were unable to reproduce this effect. Neuraxial fentanyl apparently produced its effects by a segmental spinal action. Spinal modulation of postamputation pain was important in these patients.

Rat neurons have shown an increase of spontaneously active fibers to systemically administered potassium channel blocking agents such as tetraethylammonium chloride (TEA) and gallamine. Neuroma formation and spontaneous activity have been associated with autotomy in rats and pain in humans. To evaluate the chemosensitivity of human neurons to potassium channel blocking agents, 9 subjects with neuroma pain underwent perineuromal injection in a single-blinded fashion of normal saline, gallamine, and lidocaine. Sodium had no effect on control pain levels, while gallamine significantly increased and lidocaine significantly decreased pain from control levels. Three of 4 patients with accompanying phantom limb pain noted an increase in pain after the injection of gallamine. The data suggest that peripheral input plays a modulating but not solitary role in both neuroma and phantom limb pain. Agents which increase potassium channel permeability or decrease sodium influx would be predicted to decreased perceived pain.

Two trials of chlorprothixene were carried out, mainly on patients with moderate to severe post-herpetic neuralgia. When the drug was given as 50 mg b.d. to outpatients, unpleasant side-effects were more important than slight effects in alleviating pain. When the drug was given as 50 mg 6 hourly to inpatients for 5 days only, there was alleviation of constant chronic pain in a third of the patients; the effect is still lasting over a period of months in a few patients. The side-effects during the course of treatment are prominent. It is concluded that the drug is worth trying in the course recommended by Farber and Burks [1] when other means of controlling postherpetic neuralgia have failed. It would be best to give the course only to inpatients.