Cortical Reorganization after Limb Loss: Bridging the Gap between Basic Science and Clinical Recovery.

Despite the increasing incidence and prevalence of amputation across the globe, individuals with acquired limb loss continue to struggle with functional recovery and chronic pain. A more complete understanding of the motor and sensory remodeling of the peripheral and central nervous system that occurs postamputation may help advance clinical interventions to improve the quality of life for individuals with acquired limb loss. The purpose of this article is to first provide background clinical context on individuals with acquired limb loss and then to provide a comprehensive review of the known motor and sensory neural adaptations from both animal models and human clinical trials. Finally, the article bridges the gap between basic science researchers and clinicians that treat individuals with limb loss by explaining how current clinical treatments may restore function and modulate phantom limb pain using the underlying neural adaptations described above. This review should encourage the further development of novel treatments with known neurological targets to improve the recovery of individuals postamputation.Significance Statement In the United States, 1.6 million people live with limb loss; this number is expected to more than double by 2050. Improved surgical procedures enhance recovery, and new prosthetics and neural interfaces can replace missing limbs with those that communicate bidirectionally with the brain. These advances have been fairly successful, but still most patients experience persistent problems like phantom limb pain, and others discontinue prostheses instead of learning to use them daily. These problematic patient outcomes may be due in part to the lack of consensus among basic and clinical researchers regarding the plasticity mechanisms that occur in the brain after amputation injuries. Here we review results from clinical and animal model studies to bridge this clinical-basic science gap.

Ultrasound-guided Percutaneous Cryoneurolysis to Treat Chronic Postamputation Phantom Limb Pain: A Multicenter Randomized Controlled Trial.

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.

Chronic post amputation pain: pathophysiology and prevention options for a heterogenous phenomenon.

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.

Immediate Effects of a Continuous Peripheral Nerve Block on Postamputation Phantom and Residual Limb Pain: Secondary Outcomes From a Multicenter Randomized Controlled Clinical Trial.

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.

The demographics of persistent opioid consumption following limb amputation.

BACKGROUND: Patients who have limb amputation are at risk of chronic pain, including phantom limb pain that can be challenging to treat. The aim of this study was to describe the incidence of pre-operative opioid usage and the incidence and risk factors for new persistent post-operative opioid usage in opioid-naïve patients after limb amputation. METHODS: A retrospective study of all patients 18 years and older underwent upper or lower extremity amputations in Landspitali University Hospital between 2005 and 2015. Patients were considered to use opioids pre-operatively if they filled an opioid prescription 1-6 months prior to amputation and were considered to have persistent opioid use if opioid prescriptions were filled between post-operative months four to twenty-four. In addition to incidence estimate, uni- and multivariate analysis was performed to identify risk factors for persistent post-operative opioid usage. RESULTS: Of 328 total patients, 216 (66%) were opioid naïve and 112 (34%) were chronic opioid users. Of the opioid-naïve patients surviving more than 3 months 40 (20%) developed persistent post-operative opioid usage. In multivariate analysis, factors independently associated with persistent post-operative opioid usage were younger age, male gender, pre-operative use of neuropathic medications or benzodiazepines and lower (opposed to upper) extremity amputation. CONCLUSION: Opioid naïve patients undergoing major amputation had a 20% chance of having a persistent opioid requirement following surgery. This could represent new-onset phantom limb pain or other chronic pain. Our findings should encourage perioperative multimodal efforts to reduce the burden of chronic pain after limb amputations.

[Perioperative measures for prevention of phantom pain: an evidence-based approach to risk reduction]. / Perioperative Maßnahmen zur Prävention von Phantomschmerz: ein evidenzbasierter Ansatz zur Risikoreduktion.

Prevention of phantom limb pain is one of the biggest and still largely unsolved challenges in perioperative medicine. Despite many study efforts and optimization of postoperative pain treatment over the last 30 years, a significant reduction in the incidence of phantom limb pain has not been achieved. Current studies have also shown that at least 50% of patients develop phantom pain after 6 months. A possible approach could be to combine multiple synergistic interventions and implement them as a perioperative phantom pain management strategy bundle. In addition to regional anesthesia, NMDA antagonists, gabapentinoids, antidepressants and systemic lidocaine could play a relevant role. The aim of this pharmacological intervention was the modification of the pathophysiological changes in peripheral nerves and in the central nervous system after amputation.

[Alcohol Injection in a Patient with Chronic Orbital Pain after Enucleation - a Case Report and Review of the Literature]. / Alkoholinjektion bei chronischem orbitalem Schmerz nach Enukleation ­ Falldarstellung und Literaturübersicht.

A case is presented of a 54-year old patient who had been treated 10 months previously with enucleation for a painful blind eye. This led to severe and chronic pain in the orbital region that did not respond to conventional pain management. However, a single 1.5 ml injection of 96 % ethanol led to almost complete resolution of pain for the follow-up period of 6 months. Orbital pain after enucleation or evisceration may originate from the implant itself, the prosthesis, the socket or the sinuses. Taking a careful medical history and an examination, including orbital scans, are necessary to decide on the correct differential diagnosis. If any pathology is excluded, one should keep in mind that phantom pain in the orbit seems common after removing an eye, more often when pain originating from the ball and/or headache was present before removal. The management of chronic pain in the orbital region has received little attention. Retrobulbar alcohol injection still has a place in modern ophthalmology, because it delivers effective pain relief in certain chronic conditions.

Pharmacologic interventions for treating phantom limb pain.

BACKGROUND: This is an updated version of the original Cochrane review published in Issue 12, 2011. Phantom limb pain (PLP) is pain that arises in the missing limb after amputation and can be severe, intractable, and disabling. Various medications have been studied in the treatment of phantom pain. There is currently uncertainty in the optimal pharmacologic management of PLP. OBJECTIVES: This review aimed to summarise the evidence of effectiveness of pharmacologic interventions in treating PLP. SEARCH METHODS: For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library), MEDLINE, and Embase for relevant studies. We ran the searches for the original review in September 2011 and subsequent searches for this update up to April 2016. We sought additional studies from clinical trials databases and reference lists of retrieved papers. SELECTION CRITERIA: We included randomised and quasi-randomised trials studying the effectiveness of pharmacologic interventions compared with placebo, another active treatment, or no treatment, in established PLP. We considered the following outcomes: change in pain intensity, function, sleep, depression or mood, quality of life, adverse events, treatment satisfaction, and withdrawals from the study. DATA COLLECTION AND ANALYSIS: We independently assessed issues of study quality and extracted efficacy and adverse event data. Due to the wide variability in the studies, we did not perform a meta-analysis for all the interventions and outcomes, but attempted to pool the results of some studies where possible. We prepared a qualitative description and narrative summary of results. We assessed clinical heterogeneity by making qualitative comparisons of the populations, interventions, outcomes/outcome measures, and methods. MAIN RESULTS: We added only one new study with 14 participants to this updated review. We included a 14 studies (10 with low risk of bias and 4 with unclear risk of bias overall) with a total of 269 participants. We added another drug class, botulinum neurotoxins (BoNTs), in particular botulinum toxin A (BoNT/A), to the group of medications reviewed previously. Our primary outcome was change in pain intensity. Most studies did not report our secondary outcomes of sleep, depression or mood, quality of life, treatment satisfaction, or withdrawals from the study.BoNT/A did not improve phantom limb pain intensity during the six months of follow-up compared with lidocaine/methylprednisolone.Compared with placebo, morphine (oral and intravenous) was effective in decreasing pain intensity in the short term with reported adverse events being constipation, sedation, tiredness, dizziness, sweating, voiding difficulty, vertigo, itching, and respiratory problems.The N-methyl D-aspartate (NMDA) receptor antagonists ketamine (versus placebo; versus calcitonin) and dextromethorphan (versus placebo), but not memantine, had analgesic effects. The adverse events of ketamine were more serious than placebo and calcitonin and included loss of consciousness, sedation, hallucinations, hearing and position impairment, and insobriety.The results for gabapentin in terms of pain relief were conflicting, but combining the results favoured treatment group (gabapentin) over control group (placebo) (mean difference -1.16, 95% confidence interval -1.94 to -0.38; 2 studies). However, gabapentin did not improve function, depression score, or sleep quality. Adverse events experienced were somnolence, dizziness, headache, and nausea.Compared with an active control benztropine mesylate, amitriptyline was not effective in PLP, with dry mouth and dizziness as the most frequent adverse events based on one study.The findings for calcitonin (versus placebo; versus ketamine) and local anaesthetics (versus placebo) were variable. Adverse events of calcitonin were headache, vertigo, drowsiness, nausea, vomiting, and hot and cold flushes. Most of the studies were limited by their small sample sizes. AUTHORS' CONCLUSIONS: Since the last version of this review, we identified another study that added another form of medical therapy, BoNTs, specifically BoNT/A, to the list of pharmacologic interventions being reviewed for clinical efficacy in phantom limb pain. However, the results of this study did not substantially change the main conclusions. The short- and long-term effectiveness of BoNT/A, opioids, NMDA receptor antagonists, anticonvulsants, antidepressants, calcitonins, and local anaesthetics for clinically relevant outcomes including pain, function, mood, sleep, quality of life, treatment satisfaction, and adverse events remain unclear. Based on a small study, BoNT/A (versus lidocaine/methylprednisolone) does not decrease phantom limb pain. Morphine, gabapentin, and ketamine demonstrate favourable short-term analgesic efficacy compared with placebo. Memantine and amitriptyline may not be effective for PLP. However, results must be interpreted with caution, as they were based mostly on a small number of studies with limited sample sizes that varied considerably and also lacked long-term efficacy and safety outcomes. The direction of efficacy of calcitonin, local anaesthetics, and dextromethorphan needs further clarification. Overall, the efficacy evidence for the reviewed medications is thus far inconclusive. Larger and more rigorous randomised controlled trials are needed for us to reach more definitive conclusions about which medications would be useful for clinical practice.

A Clinical Evaluation of Postamputation Phenomena Including Phantom Limb Pain after Lower Limb Amputation in Dysvascular Patients.

To explore the effects of phantom phenomena on a group of dysvascular lower limb amputees. This was a cross-sectional study of dysvascular lower limb amputees. A modified version of the phantom phenomena questionnaire was used to measure the prevalence of phantom phenomena and the effects of those phenomena on daily life. Eighty-nine amputees were recruited. The majority were inpatients (72%) and male (72%). Most had pain before amputation (83%). Sixty-three percent had phantom limb pain. No associations were found between phantom limb pain and preamputation pain (p = .397). Phantom limb pain was present immediately on waking from amputation in 23%. Phantom limb pain is highly fluctuant. It is more likely that phantom limb pain was present with more time passed since amputation (p = .002). Outpatients with unhealed wounds were less likely to have phantom limb pain (p = .007). The effects of postamputation phenomena include sleep loss and social restrictions. These results challenge the belief that phantom limb pain reduces over time as more outpatients reported phantom limb pain than inpatients. Preamputation pain is not linked to the presence of phantom limb pain. The fluctuant nature of phantom limb pain makes its treatment complex. Some may wish intensity to reduce, whereas others may prefer to reduce the number of episodes or duration of each episode instead. More research is needed to clarify the needs of amputees in relation to the postamputation phenomena.

Phantom limb pain: a systematic neuroanatomical-based review of pharmacologic treatment.

OBJECTIVE: Review the current evidence-based pharmacotherapy for phantom limb pain (PLP) in the context of the current understanding of the pathophysiology of this condition. DESIGN: We conducted a systematic review of original research papers specifically investigating the pharmacologic treatment of PLP. Literature was sourced from PubMed, Embase, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL). Studies with animals, "neuropathic" but not "phantom limb" pain, or without pain scores and/or functional measures as primary outcomes were excluded. A level of evidence 1-4 was ascribed to individual treatments. These levels included meta-analysis or systematic reviews (level 1), one or more well-powered randomized, controlled trials (level 2), retrospective studies, open-label trials, pilot studies (level 3), and anecdotes, case reports, or clinical experience (level 4). RESULTS: We found level 2 evidence for gabapentin, both oral (PO) and intravenous (IV) morphine, tramadol, intramuscular (IM) botulinum toxin, IV and epidural Ketamine, level 3 evidence for amitriptyline, dextromethorphan, topiramate, IV calcitonin, PO memantine, continuous perineural catheter analgesia with ropivacaine, and level 4 evidence for methadone, intrathecal (IT) buprenorphine, IT and epidural fentanyl, duloxetine, fluoxetine, mirtazapine, clonazepam, milnacipran, capsaicin, and pregabalin. CONCLUSIONS: Currently, the best evidence (level 2) exists for the use of IV ketamine and IV morphine for the short-term perioperative treatment of PLP and PO morphine for an intermediate to long-term treatment effect (8 weeks to 1 year). Level 2 evidence is mixed for the efficacy of perioperative epidural anesthesia with morphine and bupivacaine for short to long-term pain relief (perioperatively up to 1 year) as well as for the use of gabapentin for pain relief of intermediate duration (6 weeks).

Phantom eye syndrome: a review of the literature.

The purpose of this literature review was to describe the main features of phantom eye syndrome in relation to their possible causes, symptoms, treatments, and influence of eye amputation on quality of life of anophthalmic patients. For this, a bibliographical research was performed in Pubmed database using the following terms: "eye amputation," "eye trauma," "phantom eye syndrome," "phantom pain," and "quality of life," associated or not. Thirteen studies were selected, besides some relevant references contained in the selected manuscripts and other studies hallowed in the literature. Thus, 56 articles were included in this review. The phantom eye syndrome is defined as any sensation reported by the patient with anophthalmia, originated anophthalmic cavity. In phantom eye syndrome, at least one of these three symptoms has to be present: phantom vision, phantom pain, and phantom sensations. This syndrome has a direct influence on the quality of life of the patients, and psychological support is recommended before and after the amputation of the eyeball as well as aid in the treatment of the syndrome. Therefore, it is suggested that, for more effective treatment of phantom eye syndrome, drug therapy should be associated with psychological approach.

[Capsaicin 8 % cutaneous patches for phantom limb pain. Results from everyday practice (non-interventional study)]. / Das 8 %ige Capsaicin-Pflaster bei Phantomschmerz. Ergebnisse aus dem Praxisalltag (nichtinterventionelle Studie).

BACKGROUND: Post amputation pain presents a challenge for pain physicians and is often detrimental to the patient's quality of life. PATIENTS AND METHODS: A prospective 12-week non-interventional study (NIS) was conducted in Germany to obtain data on the effectiveness and safety of capsaicin 8 % cutaneous patches from real life use in patients with peripheral neuropathic pain. For the first time in a subgroup of amputees data on post amputation pain were collected. This article presents the results for patients who suffered from phantom limb pain (PLP), stump pain (SP) and combined phantom limb/stump pain (PLP/SP). RESULTS: The analyses included 21 patients with post amputation pain (PLP: n = 10, SP: n = 4, PLP/SP: n = 7). The mean duration of pain (± standard deviation) was 12.8 ± 13.0 years for PLP, 23.1 ± 29.9 years for SP and 11.0 ± 15.8 years for PLP/SP. A single treatment with capsaicin 8 % cutaneous patches significantly reduced the average pain intensity over the observational period of 12 weeks. The mean numeric pain rating scale (NPRS) baseline score changed by - 2.4 for PLP with a standard error of the mean (SEM) of 0.4 (median: - 2.9, Q1: - 3.5, Q3: - 1.0), - 1.7 for SP (SEM: 0.8, median: - 1.1, Q1: - 2.9, Q3: - 0.5) and - 1.5 for PLP/SP (SEM: 0.6, median: - 2.0, Q1: - 2.3, Q3: 0) during weeks 1-12. The 30 % responder rates (i.e. ≥ 30 % reduction in pain, day 7/14 to week 12) were 70.0 % (PLP), 50.0 % (SP) and 28.6 % (PLP/SP). PLP and PLP/SP patients in particular, benefited from improvements in pain attacks, sleep duration and sleep quality and one patient (PLP/SP) reported an adverse drug reaction (increase of pain). Physicians rated the tolerability of the patch as very good or good in 90.5 % of patients. A poor tolerability was stated for none of the 21 amputees. Of the patients 80 % for PLP and 50 % for both SP and PLP/SP expressed the wish to receive retreatment with capsaicin 8 % patches. CONCLUSION: Capsaicin 8 % cutaneous patches seem to be effective and safe for the treatment of post amputation pain, notably in patients suffering from phantom limb pain.

Treating intractable phantom limb pain with ambulatory continuous peripheral nerve blocks: a pilot study.

BACKGROUND: There is currently no reliable treatment for phantom limb pain (PLP). Chronic PLP and associated cortical abnormalities may be maintained from abnormal peripheral input, raising the possibility that a continuous peripheral nerve block (CPNB) of extended duration may permanently reorganize cortical pain mapping, thus providing lasting relief. METHODS: Three men with below-the-knee (2) or -elbow (1) amputations and intractable PLP received femoral/sciatic or infraclavicular perineural catheter(s), respectively. Subjects were randomized in a double-masked fashion to receive perineural ropivacaine (0.5%) or normal saline for over 6 days as outpatients using portable electronic infusion pumps. Four months later, subjects returned for repeated perineural catheter insertion and received an ambulatory infusion with the alternate solution ("crossover"). Subjects were followed for up to 1 year. RESULTS: By chance, all three subjects received saline during their initial infusion and reported little change in their PLP. One subject did not receive crossover treatment, but the remaining two subjects reported complete resolution of their PLP during and immediately following treatment with ropivacaine. One subject experienced no PLP recurrence through the 52-week follow-up period and the other reported mild PLP occurring once each week of just a small fraction of his original pain (pretreatment: continuous PLP rated 10/10; posttreatment: no PLP at baseline with average of one PLP episode each week rated 2/10) for 12 weeks (lost to follow-up thereafter). CONCLUSIONS: A prolonged ambulatory CPNB may be a reliable treatment for intractable PLP. The results of this pilot study suggest that a large, randomized clinical trial is warranted.

An observational descriptive study of the epidemiology and treatment of neuropathic pain in a UK general population.

BACKGROUND: This study updated our knowledge of UK primary care neuropathic pain incidence rates and prescribing practices. METHODS: Patients with a first diagnosis of post-herpetic neuralgia (PHN), painful diabetic neuropathy (PDN) or phantom limb pain (PLP) were identified from the General Practice Research Database (2006 - 2010) and incidence rates were calculated. Prescription records were searched for pain treatments from diagnosis of these conditions and the duration and daily dose estimated for first-line and subsequent treatment regimens. Recording of neuropathic back and post-operative pain was investigated. RESULTS: The study included 5,920 patients with PHN, 5,340 with PDN, and 185 with PLP. The incidence per 10,000 person-years was 3.4 (95% CI 3.4, 3.5) for PHN; and 0.11 (95% CI 0.09, 0.12) for PLP. Validation of the PDN case definition suggested that was not sensitive. Incident PHN increased over the study period. The most common first-line treatments were amitriptyline or gabapentin in the PDN and PLP cohorts, and amitriptyline or co-codamol (codeine-paracetamol) in PHN. Paracetamol, co-dydramol (paracetamol-dihydrocodeine) and capsaicin were also often prescribed in one or more condition. Most first-line treatments comprised only one therapeutic class. Use of antiepileptics licensed for neuropathic pain treatment had increased since 2002-2005. Amitriptyline was the only antidepressant prescribed commonly as a first-line treatment. CONCLUSION: The UK incidence of diagnosed PHN has increased with the incidence of back-pain and post-operative pain unclear. While use of licensed antiepileptics increased, prescribing of therapy with little evidence of efficacy in neuropathic pain is still common and consequently treatment was often not in-line with current guidance.

[Prolonged-release tapentadol for phantom pain. A case series]. / Retardiertes Tapentadol bei Phantomschmerzen. Eine Fallserie.

OBJECTIVES: The successful therapy of phantom pain remains a major challenge, because the underlying pathophysiological mechanisms are still not fully understood. A therapeutic approach with tapentadol has not been described so far. PATIENTS AND METHODS: Five patients suffering upper and lower extremity phantom pain were successfully treated with tapentadol (prolonged release) with differing doses. RESULTS: In 4 patients, a strongly reduced pain intensity between 4 and 6.5 on the visual analog scale (VAS) was recorded. The fifth patient reported an increase in the nocturnal sleep duration from 2 to 5 h and a decrease in the number of phantom pain attacks by 30 %. In 2 patients, the additional medication could be lowered or stretched. Side effects (vertigo, fatigue) were only observed in one subject. CONCLUSION: The cases described provide preliminary evidence that the synergistic combination of µ-opioid receptor agonism (MOR) and noradrenalin re-uptake inhibition (NRI) provided by tapentadol may be beneficial in the treatment of phantom pain.

Atypical odontalgia: an up-to-date view.

Atypical odontalgia (AO) is a little known chronic pain condition. It usually presents as pain in a site where a tooth was endodontically treated or extracted, in the absence of clinical or radiographic evidence of tooth pathology. It is a rare clinical challenge for most clinicians, which leads to the patients being referred to several specialists and sometimes undergoing unnecessary surgical procedures. The pain mechanisms involved in AO are far from clear, and numerous potential mechanisms have been suggested. Currently, the most accredited hypothesis is that AO is a neuropathic pain condition caused by deafferentation. The differential diagnosis of AO remains difficult, because it shares symptoms with many others pathologies affecting this area. Patients have difficulties accepting the AO diagnosis and treatment. As a result, they frequently change physicians, and may potentially also receive several invasive treatments, usually resulting in an aggravation of the pain. Although some patients do get complete pain relief following treatment, for most patients the goal should be to achieve adequate pain management. Currently, most management is based on expert opinion and case reports. More research and high quality randomized controlled trials are needed in order to develop evidence-based treatments, currently based on expert opinion or carried over from other neuropathic pain conditions in the orofacial region.

Effect of mirror therapy in the treatment of phantom limb pain in amputees: A systematic review of randomized placebo-controlled trials does not find any evidence of efficacy.

BACKGROUND AND OBJECTIVE: Phantom limb pain (PLP) concerns >50% of amputees and has a negative impact on their rehabilitation, mental health and quality of life. Mirror therapy (MT) is a promising strategy, but its effectiveness remains controversial. We performed a systematic review to: (i) evaluate the effectiveness of MT versus placebo in reducing PLP, and (ii) determine MT effect on disability and quality of life. DATABASES AND DATA TREATMENT: We selected randomized-controlled trials in five databases (Medline, Cochrane Library, CINAHL, PEDro and Embase) that included patients with unilateral lower or upper limb amputation and PLP and that compared the effects on PLP of MT versus a placebo technique. The primary outcome was PLP intensity changes and the secondary outcomes were PLP duration, frequency, patients' disability and quality of life. RESULTS: Among the five studies included, only one reported a significant difference between the MT group and control group, with a positive MT effect at week 4. Only one study assessed MT effect on disability and found a significant improvement in the MT group at week 10 and month 6. CONCLUSIONS: Our systematic review did not allow concluding that MT reduces PLP and disability in amputees. This lack of strong evidence is probably due to (i) the low methodological quality of the included studies, and (ii) the lack of statistical power. Future trials should include a higher number of patients, increase the number and frequency of MT sessions, have a long-term follow-up and improve the methodological quality. SIGNIFICANCE: Recent meta-analyses concluded that MT is effective for reducing phantom limb pain. Conversely, the present systematic review that included only studies with the best level of evidence did not find any evidence about its effectiveness for this condition. We identified many ways to improve future randomized-controlled trials on this topic: increasing the number of participants, reducing the intra-group heterogeneity, using a suitable placebo and intensifying the MT sessions and frequency.

Calcitonin in the Treatment of Phantom Limb Pain: A Systematic Review.

INTRODUCTION: Phantom limb pain (PLP) refers to pain perceived in a part of the body removed by amputation or trauma. Despite the high prevalence of PLP following amputation and the significant morbidity associated with it, robust therapeutic approaches are currently lacking. Calcitonin, a polypeptide hormone, has recently emerged as a novel analgesic with documented benefits in the treatment of several pain-related conditions. METHODS: We present a systematic review that comprehensively evaluates the analgesic effects of calcitonin for patients with PLP. We searched MEDLINE, OLDMEDLINE, and PubMed Central databases with the key words "calcitonin" "phantom limb pain" and "phantom pain" to identify clinical studies evaluating the efficacy or effectiveness of calcitonin administration, in any form and dose, for the treatment of PLP. Additionally, Google Scholar was searched manually with the search term "calcitonin phantom limb pain". All four databases were searched from inception until 1 December 2022. The methodological quality of each included study was assessed using the Downs and Black checklist and the GRADE criteria were used to assess effect certainty and risk of bias. RESULTS: Our search identified 4108 citations, of which six ultimately met the criteria for inclusion in the synthesis. The included articles described a mix of open-label (n = 2), prospective observational cohort (n = 1), and randomized clinical trials (n = 3). The most common treatment regimen in the current literature is a single intravenous infusion of 200 IU salmon-derived calcitonin. CONCLUSION: The available evidence supported the use of calcitonin as either monotherapy or adjuvant therapy in the treatment of PLP during the acute phase, while the evidence surrounding calcitonin treatment in chronic PLP is heterogeneous. Given the limited treatment options for the management of PLP and calcitonin's relatively wide therapeutic index, further research is warranted to determine the role that calcitonin may play in the treatment of PLP and other pain disorders.

Perioperative Management of Painful Phantom Limb Syndrome: A Narrative Review and Clinical Management Proposal.

OBJECTIVE: Painful Phantom Limb Syndrome (PPLS) occurs in 50 to 80% of patients undergoing amputation, having a great impact on quality of life, productivity and psychosocial sphere. The objective of this review is to summarize the pharmacological and non-pharmacological strategies, surgical optimization, and provide a multidisciplinary approach aimed at reducing the incidence of chronic pain associated with PPLS in patients undergoing limb amputation. METHODS: A narrative review was carried out using Medline, Pubmed, Proquest, LILACS and Cochrane, searching for articles between 2000 and 2021. Articles describing the epidemiology, pathophysiological considerations, and current treatments were selected after a screening process. RESULTS: A multidisciplinary and multimodal approach is required in PPLS, and should include the use of regional techniques, and adjuvants such as NSAIDs, ketamine, lidocaine and gabapentinoids. In addition, an evaluation and continuous management of risk factors for chronic pain in conjunction with the surgical team is necessary. CONCLUSION: The current literature does not support that a single technique is effective inthe prevention of PPLS. However, adequate acute pain control, rehabilitation and early restoration of the body scheme under a multidisciplinary and multimodal approach have shown benefit in the acute setting.