Prevention and control of chronic post-amputation pain of extremities: systematic review

Nycole Filincowsky Ribeiro Xavier Jéssica Cristina Farias de Almeida Priscilla Roberta Silva Rocha Mani Indiana Funez About the authors

ABSTRACT

BACKGROUND AND OBJECTIVES:

Post-amputation pain is very frequent and can become chronic in almost 85% of the cases. The objective of this study was to conduct a systematic review concerning the evidence about the measures for the control or remission of chronic pain in the stump or phantom limb in adults and the elderly after extremity amputation.

CONTENTS:

The search was conducted in the databases Pubmed, Mendeley, Livivo, and Science Direct. Additional searches were performed at ClinicalTrial.gov, Google Scholar, and in the references of the selected articles. Two independent reviewers performed the screening of the studies as well as the data extraction and synthesis. The Cochrane Collaboration Risk of Bias Tool was used to analyze the risk of bias, and four articles were identified. Two articles on pharmacological prevention strategies and two articles on non-pharmacological treatment. The risk of bias was low for the pharmacological approach, and uncertain or high for the non-pharmacological.

CONCLUSION:

The findings suggest a protective effect of preventive pharmacological therapies, epidurally, in combination with bupivacaine and fentanyl or added to calcitonin, in the perioperative period. Promising data are also presented for non-pharmacological therapies for pain control, phantom motor execution and gradual motor images. However, caution is necessary due to the risk of bias and considering the number of studies that answer the research question. Additional studies are suggested to strengthen the evidence, especially with quantitative analysis.

Keywords:
Amputation; Perioperative period; Phantom limb; Postoperative pain; Therapeutics

RESUMO

JUSTIFICATIVA E OBJETIVOS:

A dor pós-amputação tem alta prevalência, podendo tornar-se crônica em até 85% dos casos. O objetivo deste estudo foi analisar as evidências acerca de medidas para o controle ou remissão da dor crônica no coto ou membro fantasma em adultos e idosos com amputação de extremidades.

CONTEÚDO:

Realizaram-se buscas nas bases Pubmed, Mendeley, Livivo e Science Direct. Buscas adicionais foram realizadas na página eletrônica ClinicalTrial.gov, Google Scholar e listas de referências dos artigos selecionados. A triagem dos estudos, bem como a extração e síntese dos dados, foi realizada por dois revisores independentes. A análise do risco de viés foi feita pela Cochrane Collaboration Risk of Bias Tool, sendo identificados quatro estudos. Dois sobre estratégias de prevenção farmacológica, e dois sobre estratégias de tratamento não farmacológico. O risco de viés foi baixo para as abordagens farmacológicas, e incerto ou alto para as abordagens não farmacológicas.

CONCLUSÃO:

Os achados sugerem efeito protetor das terapias farmacológicas preventivas, por via peridural, em combinação de bupivacaína e fentanil ou somados à calcitonina, no período perioperatório. Dados promissores também são apresentados para as terapias não farmacológicas de controle da dor, execução motora fantasma e imagens motoras gradativas. Porém, é necessário prudência devido ao risco de viés e considerando a quantidade de estudos que respondem a pergunta de pesquisa. Sugerem-se estudos adicionais para fortalecer as evidências, especialmente com análise quantitativa.

Descritores:
Amputação; Dor pós-operatória; Membro fantasma; Período perioperatório; Terapêutica

INTRODUCTION

Amputation is the removal of all or part of a limb. In Brazil, between 2008 and 2015, the Hospital Information System of the Unified Health System recorded 361,585 amputations, approximately 4,304 amputations per month11 Peixoto AM, Zimpel SA, Oliveira ACA, Monteiro RLS, Carneiro TKG. Prevalence of upper and lower limb amputations of SUS patients in the state of Alagoas between 2008 and 2015. Fisioter Pesqui. 2017;24(4):378-84.. In the United States, it is estimated that by 2050, approximately 1,6 million people will undergo this procedure22 Ahuja V, Thapa D, Ghai B. Strategies for prevention of lower limb post-amputation pain: a clinical narrative review. J Anaesthesiol Clin Pharmacol. 2018;34(4):439-49.. Among the most common causes of amputation are trauma, diabetes mellitus, peripheral vascular diseases, and tumors33 Kumar GK, Souza CD, Diaz EA. Incidence and causes of lower-limb amputations in a tertiary care center: evaluation of the medical records in a period of 2 years. Int J Surg Sci. 2018;2(3):16-9.

4 International Association for the Study of Pain. Postamputation Pain. Global Year Against Neuropathic Pain. 2014-2015.
-55 Nikolajsen L. "Phantom limb," in Wall and Melzack's Textbook of Pain, SB. McMahon PD, Wall RM (Eds). Philadelphia: Elsevier, Saunders, PA, USA; 2013..

Amputees are patients who have a high prevalence of post-surgical pain, about 70% have some type of pain that can be intense in up to 15% of the cases44 International Association for the Study of Pain. Postamputation Pain. Global Year Against Neuropathic Pain. 2014-2015., and acute or chronic, depending on the duration. Post-amputation pain can be of two kinds, which many times coexist in the same patient: residual limb or stump pain (SP), and the phantom limb pain (PLP), a painful sensation in the surgically removed limb or part of it55 Nikolajsen L. "Phantom limb," in Wall and Melzack's Textbook of Pain, SB. McMahon PD, Wall RM (Eds). Philadelphia: Elsevier, Saunders, PA, USA; 2013..

It is estimated that 50 to 85% of the amputees develop chronic post-amputation pain (CPAP)66 Taylan A, Derya Ö. Chronic post-surgical pain. Agri. 2009;21(1):1-9.. Four primary criteria are used to diagnose. Initial pain after the surgical procedure - however, on amputation, the presence of pain before surgery is not exclusionary, being a characteristic of the chronicity that after amputation the pain remains or even worsens; persistent for a variable period from two to six months or more; with the factors that have led to amputation no longer present in the individual, and not related to the natural course of the disease - as in the oncologic cases55 Nikolajsen L. "Phantom limb," in Wall and Melzack's Textbook of Pain, SB. McMahon PD, Wall RM (Eds). Philadelphia: Elsevier, Saunders, PA, USA; 2013.,77 Posso IP, Romanek RM, Posso JP, Carvalho M. Dor Crônica Pós-Operatória. In: Posso IP, Grossmann E, Fonseca PRB, Perissinotti DMN, Oliveira Junior JO, Souza JB et al. Tratado de Dor: Publicação da Sociedade Brasileira para Estudo da Dor. 1ª ed. Rio de Janeiro: Atheneu; 2017. 699p..

Since it is a potentially disabling condition, which pathophysiology is not fully understood, effective strategies to prevent and manage post-amputation pain are challenges to overcome as there is no consensus about the most effective and efficient way to address it88 Yaputra F, Widyadharma IPE. Management of phantom limb pain: a review. Int J Med Rev Case Rep. 2018;2(2):29-32..

The objective of this study was to gather evidence on the control or remission of the chronic stump or phantom limb pain in adults and the elderly with amputation of extremities.

CONTENTS

This systematic review followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA checklist)99 Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4(1):1-9. and the Synthesis Without Meta-analysis (SWiM) guideline1010 Campbell M, McKenzie JE, Sowden A, Katikireddi SV, Brennan SE, Ellis S, et al. Synthesis without meta-analysis (SWiM) in systematic reviews: reporting guideline. BMJ. 2020;368:l6890. The protocol is registered in the International Prospective Register of Systematic Reviews (PROSPERO 2020 CRD42020151543). The question of the study was defined according to the PICO acronym1111 da Costa Santos CM, de Mattos Pimenta CA, Nobre MR. The PICO strategy for the research question construction and evidence search. Rev Lat Am Enfermagem. 2007;15(3):508-11.. "What is the evidence in the literature about measures to control chronic pain (stump or phantom limb) in adult and elderly patients with amputation of extremities"?

Clinical trials with preventive and/or therapeutic approach conducted with humans were included, with no language restriction, that addressed pharmacological and non-pharmacological interventions to prevent and manage post-amputation pain in adults or elderly patients, with outcomes of interest on chronic pain, stump pain and phantom pain, published between 2009 and 2019. Reviews, meta-analysis, case reports, and case series were excluded.

Information source and search strategy

The electronic databases Livivo, Mendeley, Pubmed and Science Direct were consulted on 08/07/2019. The search strategy was established according to the PICO strategy described above, adapted for each base ("amputation" OR "amputation stumps" OR "extremities amputation" OR "amputees" OR "limb amputation") AND ("Drug therapy" OR "non-pharmacological therapy" OR "pharmacological therapy") AND ("chronic pain" OR "Pain" OR "Pain, intractable" OR "Phantom limb") (Appendix 2). In addition, a search was performed in the records of the ClinicalTrial.gov website and in the gray literature (Google Scholar). The manual search in the reference lists of the selected articles did not show articles that could be analyzed within the scope of this study.

Selection of the studies

Two revisors read the titles and abstracts of the studies identified in the search. The studies that met the inclusion criteria were fully read and analyzed by the revisors. A third revisor solved the discrepancies in the selection, and those studies that did not meet the inclusion criteria were excluded.

Process of data collection

Two revisors collected the data independently with the general characteristics of the study including author, year, location, objective, design, characteristics of the therapy used - prevention or treatment, pharmacological or non-pharmacological, characteristics of the pain, intensity, site, type - SP or PLP, characteristics of the amputation, site of the surgical procedure, cause, and outcome with the respective results. A third revisor solved the discrepancies in the collection.

Risk of Bias analysis

The risk of bias of the studies included in the review was assessed by the Cochrane - Risk of Bias Tools (ROB)®1212 Sterne JAC, Savovic J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898.. It is a two-step assessment tool that assesses seven domains concerning the generation of the random sequence, blinding of participants and professionals, blinding of the outcome assessors, incomplete outcomes, report of the selective outcome, and other sources of bias. The first step assessed the existence of enough details to make a judgment based on the information provided. The second step judged the risk of bias of each of the domains that were then classified into three categories: low, high, or uncertain risk of bias1313 Carvalho APV, SilvaII V, Grande AJ. Avaliação do risco de viés de ensaios clínicos randomizados pela ferramenta da colaboração Cochrane. Diagn Tratamento. 2013;18(1):38-44.,1414 Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration. 2011. Disponível em www.handbook.cochrane.org.
www.handbook.cochrane.org...
.

Summary of the measures and synthesis of the results

The primary outcome was prevention, improvement, or total remission of CPAP, whether SP or PLP. The findings of the studies included were reported by the descriptive synthesis of the results.

The surveyed database identified 11,527 records. After removing the duplicates, 3,273 references went to the selection phase when the titles and abstracts were read. Eighteen documents were added from the reference list, exploratory search, and records on the ClinicalTrials.gov website. After reading the titles and abstracts, 35 studies were selected for full reading and eligibility assessment, of which 31 were excluded (Figure 1), and four studies made up the final sample. Figure 1 describes the process of identification, selection, eligibility, and inclusion of the studies.

Figure 1
Flowchart of the search in the literature and selection process Brasília, DF, Brazil, 2019

General characteristics of the studies

The studies selected for review were published between 2011 and 2019, in English; two studies were conducted in Europe and two in Africa. Regarding the interventions for CPAP, two studies1515 Karanikolas M, Aretha D, Tsolakis I, Monantera G, Kiekkas P, Papadoulas S, et al. Optimized perioperative analgesia reduces chronic phantom limb pain intensity, prevalence, and frequency: a prospective, randomized, clinical trial. Anesthesiology. 2011;114(5):1144-54.,1616 Yousef AA, Aborahama AM. The preventive value of epidural calcitonin in patients with lower limb amputation. Pain Med. 2017;18(9):1745-51. reported pharmacological strategy for prevention, and two studies1717 Ortiz-Catalan M, Guðmundsdóttir RA, Kristoffersen MB, Zepeda-Echavarria A, Caine-Winterberger K, Kulbacka-Ortiz K, et al. Phantom motor execution facilitated by machine learning and augmented reality as treatment for phantom limb pain: a single group, clinical trial in patients with chronic intractable phantom limb pain. Lancet. 2016;388(10062):2885-94.,1818 Limakatso K, Madden VJ, Manie S, Parker R. The effectiveness of graded motor imagery for reducing phantom limb pain in amputees: a randomised controlled trial. Physiotherapy. 2019;28. S0031-9406(18)30188-3. reported a non-pharmacological strategy (Table 1).

Table 1
Summary of the descriptive characteristics of the studies included in the review (n=4). Brasília, Distrito Federal, Brazil, 2019

Table 1 shows the data extracted. The studies were classified according to the applied intervention strategy - preventive or treatment, and its modality - pharmacological or non-pharmacological, as well as the outcome. Amputation of lower and upper limbs was reported due to vascular disease, diabetes mellitus, trauma, infection, and tumor. All studies had, at least, a follow up of six months. All studies that assessed the strategies to treat and control CPAP analyzed patients who had been in pain for more than three months1717 Ortiz-Catalan M, Guðmundsdóttir RA, Kristoffersen MB, Zepeda-Echavarria A, Caine-Winterberger K, Kulbacka-Ortiz K, et al. Phantom motor execution facilitated by machine learning and augmented reality as treatment for phantom limb pain: a single group, clinical trial in patients with chronic intractable phantom limb pain. Lancet. 2016;388(10062):2885-94.,1818 Limakatso K, Madden VJ, Manie S, Parker R. The effectiveness of graded motor imagery for reducing phantom limb pain in amputees: a randomised controlled trial. Physiotherapy. 2019;28. S0031-9406(18)30188-3..

Risk of individual bias of the studies

The risk of bias analysis showed that 50% of the analyzed articles1515 Karanikolas M, Aretha D, Tsolakis I, Monantera G, Kiekkas P, Papadoulas S, et al. Optimized perioperative analgesia reduces chronic phantom limb pain intensity, prevalence, and frequency: a prospective, randomized, clinical trial. Anesthesiology. 2011;114(5):1144-54.,1616 Yousef AA, Aborahama AM. The preventive value of epidural calcitonin in patients with lower limb amputation. Pain Med. 2017;18(9):1745-51. had a low risk of bias in their conduction, being them of CPAP prevention and pharmacological therapy. One of the studies on non-pharmacological therapy was classified as a high risk of bias because it did not provide enough information on the randomness in sequence generation, allocation of subjects, and incomplete outcomes, and data that denied the blinding of participants/professionals and outcome evaluators1717 Ortiz-Catalan M, Guðmundsdóttir RA, Kristoffersen MB, Zepeda-Echavarria A, Caine-Winterberger K, Kulbacka-Ortiz K, et al. Phantom motor execution facilitated by machine learning and augmented reality as treatment for phantom limb pain: a single group, clinical trial in patients with chronic intractable phantom limb pain. Lancet. 2016;388(10062):2885-94.. Another study was classified as an uncertain risk of bias due to insufficient information on the random sequence generation process and to assess the existence of an important risk of bias1818 Limakatso K, Madden VJ, Manie S, Parker R. The effectiveness of graded motor imagery for reducing phantom limb pain in amputees: a randomised controlled trial. Physiotherapy. 2019;28. S0031-9406(18)30188-3. (Figure 2).

Figure 2
Assessment of the risk of bias of the studies included in the review. Brasília, DF, Brazil, 2019

Results of the individual studies

One study1515 Karanikolas M, Aretha D, Tsolakis I, Monantera G, Kiekkas P, Papadoulas S, et al. Optimized perioperative analgesia reduces chronic phantom limb pain intensity, prevalence, and frequency: a prospective, randomized, clinical trial. Anesthesiology. 2011;114(5):1144-54. analyzed the impact of different pharmacological treatment regimens with a focus on the perioperative analgesia for the CPAP outcome, including SP and PLP in the lower limbs (LL). The considered perioperative period was 48h before and 48h after the amputation. Sixty-five patients were allocated in five groups (Table 1). The anesthesia varied among groups 1 to 4; epidural or general, and pre- and post-surgical analgesia with fentanyl, intravenous, and controlled by the patient, or epidural together with bupivacaine, continuous. Group 5, the control, received the standard treatment of the institution of the study (Table 1). The outcomes showed in table 1 refer to the analysis, six months after amputation. The outcome comparisons were among the treated groups and the control group (Table 1). Only group 1 - bupivacaine + epidural fentanyl (p=0.001) had a PLP intensity significantly different from the control.

Nevertheless, the prevalence of PLP was significantly different in the control group from groups 1, 2 and 4 (p=0.004) (Table 1). Given this data, and for the purpose of this review, it will be considered as a successful treatment, the one received by group 1. There was no difference in SP among the treated and the control groups.

Study1616 Yousef AA, Aborahama AM. The preventive value of epidural calcitonin in patients with lower limb amputation. Pain Med. 2017;18(9):1745-51. assessed the preventive role of calcitonin combined with bupivacaine and fentanyl epidurally for SP, analyzing hyperalgesia and allodynia, and PLP in amputations of the LL. The treatment was performed in the perioperative and every 24h, for two days after surgery. There was no preoperative treatment. Two groups were tested with 30 patients each. The control group received the same treatment protocol, with no calcitonin. Both SP and PLP were significantly lower in the group treated with calcitonin in combination (p=0.013 for allodynia and p=0.025 for hyperalgesia in SP, and p=0.001 for PLP). The prevalence of PLP was 100% in both groups.

Study1717 Ortiz-Catalan M, Guðmundsdóttir RA, Kristoffersen MB, Zepeda-Echavarria A, Caine-Winterberger K, Kulbacka-Ortiz K, et al. Phantom motor execution facilitated by machine learning and augmented reality as treatment for phantom limb pain: a single group, clinical trial in patients with chronic intractable phantom limb pain. Lancet. 2016;388(10062):2885-94. analyzed the effectiveness of the phantom motor execution with the aid of equipment to recognize myoelectrical patterns, using virtual reality, augmented reality, and gamification. The analysis compared the baseline values and the values after 12 intervention sessions. The amputations were of the upper limbs, and the individuals have had untreatable pain for an average of 10.3 years. There was a significant improvement in PLP, with a 47% reduction (p=0.001) (Table 1).

Study1818 Limakatso K, Madden VJ, Manie S, Parker R. The effectiveness of graded motor imagery for reducing phantom limb pain in amputees: a randomised controlled trial. Physiotherapy. 2019;28. S0031-9406(18)30188-3. investigated the effectiveness of a 6-week program of graded motor imagery treatment for PLP in subjects mostly with LL amputation, divided into intervention group and conventional physiotherapy control group. The group that received the intervention showed a significant reduction in PLP when compared with the control (p=0.03). In addition, the data analysis allowed to deduce that the individuals who received the intervention would have 15 times more chance to have a significant reduction in PLP than those of the control group.

It is worth noting that a meta-analysis was not conducted in this review, due to the number of studies eligible for analysis and their heterogeneous characteristics.

Summary of the results

All the studies included had results significantly different from the control groups1515 Karanikolas M, Aretha D, Tsolakis I, Monantera G, Kiekkas P, Papadoulas S, et al. Optimized perioperative analgesia reduces chronic phantom limb pain intensity, prevalence, and frequency: a prospective, randomized, clinical trial. Anesthesiology. 2011;114(5):1144-54.,1616 Yousef AA, Aborahama AM. The preventive value of epidural calcitonin in patients with lower limb amputation. Pain Med. 2017;18(9):1745-51.,1818 Limakatso K, Madden VJ, Manie S, Parker R. The effectiveness of graded motor imagery for reducing phantom limb pain in amputees: a randomised controlled trial. Physiotherapy. 2019;28. S0031-9406(18)30188-3. or the patients' baseline1717 Ortiz-Catalan M, Guðmundsdóttir RA, Kristoffersen MB, Zepeda-Echavarria A, Caine-Winterberger K, Kulbacka-Ortiz K, et al. Phantom motor execution facilitated by machine learning and augmented reality as treatment for phantom limb pain: a single group, clinical trial in patients with chronic intractable phantom limb pain. Lancet. 2016;388(10062):2885-94.. In summary, the pharmacological treatment to control pain in perioperative prevents CPAP (SP and/or PLP), showing promising results both for intensity and prevalence. However, there are still some questions that suggest the need for additional studies: 1) a regime that includes pre-surgical treatment seems to have an impact on the prevalence and intensity of PLP, reducing them1515 Karanikolas M, Aretha D, Tsolakis I, Monantera G, Kiekkas P, Papadoulas S, et al. Optimized perioperative analgesia reduces chronic phantom limb pain intensity, prevalence, and frequency: a prospective, randomized, clinical trial. Anesthesiology. 2011;114(5):1144-54., 2) a regime that includes epidural calcitonin seems to have an impact on the SP frequency and PLP intensity, but not on its prevalence1616 Yousef AA, Aborahama AM. The preventive value of epidural calcitonin in patients with lower limb amputation. Pain Med. 2017;18(9):1745-51.. The pharmacological treatment involving the phantom motor execution1717 Ortiz-Catalan M, Guðmundsdóttir RA, Kristoffersen MB, Zepeda-Echavarria A, Caine-Winterberger K, Kulbacka-Ortiz K, et al. Phantom motor execution facilitated by machine learning and augmented reality as treatment for phantom limb pain: a single group, clinical trial in patients with chronic intractable phantom limb pain. Lancet. 2016;388(10062):2885-94. or graded motor imagery1818 Limakatso K, Madden VJ, Manie S, Parker R. The effectiveness of graded motor imagery for reducing phantom limb pain in amputees: a randomised controlled trial. Physiotherapy. 2019;28. S0031-9406(18)30188-3., controls PLP, reducing its intensity. These questions still remain for these approaches: 1) it was not possible to establish the impact of these treatments for SP since it has not been addressed in the studies; 2) additional studies with a lower risk of bias may be useful for establishing more robust evidence.

DISCUSSION

Four studies met the inclusion and exclusion criteria and were grouped into subgroups according to the therapeutic strategy - prevention or treatment, and approach - if pharmacological or non-pharmacological. Pharmacological approaches were used for the prevention of CPAP, analyzing the PLP and SP outcomes. Non-pharmacological approaches were used for the treatment of CPAP, analyzing the outcomes for PLP, not mentioning SP. Despite the differences in the observed effects, the risk of bias in some studies, and the clear need for additional studies, all proposed approaches showed statistically significant benefits to the CPAP primary outcome, whether for prevention or control.

When prevention and acute pain treatment measures are applied, the incidence, prevalence, and intensity of chronic pain can be substantially minimized. In this sense, the peri, pre, intra, and post-operative multimodal pharmacological analgesia is among the most effective measures described in the literature, with the epidural use standing out for the control of the amputation-related pain55 Nikolajsen L. "Phantom limb," in Wall and Melzack's Textbook of Pain, SB. McMahon PD, Wall RM (Eds). Philadelphia: Elsevier, Saunders, PA, USA; 2013.,1919 Subedi B, Grossberg GT. Phantom limb pain: mechanisms and treatment approaches. Pain Res Treat. 2011;2011:864605.

20 Flor H. Maladaptive plasticity, memory for pain and phantom limb pain: review and suggestions for new therapies. Expert Rev Neurother. 2008;8(5):809-18.

21 Collins KL, Russell HG, Schumacher PJ, Robinson-Freeman KE, O'Connor EC, Gibney KD, et al. A review of current theories and treatments for phantom limb pain. J Clin Invest. 2018;128(6):2168-76.
-2222 Bach S, Noreng MF, Tjhllden NU. Phantom limb pain in amputees during the first 12 months following limb amputation, after preoperative lumbar epidural blockade. Pain. 1988;33(3):297-301..

In this study, it was found that the pharmacological treatment of continuous perioperative analgesia with a bolus dose of bupivacaine, fentanyl plus calcitonin, both epidurally, prevented the development of PLP in a significant number of subjects1515 Karanikolas M, Aretha D, Tsolakis I, Monantera G, Kiekkas P, Papadoulas S, et al. Optimized perioperative analgesia reduces chronic phantom limb pain intensity, prevalence, and frequency: a prospective, randomized, clinical trial. Anesthesiology. 2011;114(5):1144-54., and those who have developed it, the pain intensity was lower1515 Karanikolas M, Aretha D, Tsolakis I, Monantera G, Kiekkas P, Papadoulas S, et al. Optimized perioperative analgesia reduces chronic phantom limb pain intensity, prevalence, and frequency: a prospective, randomized, clinical trial. Anesthesiology. 2011;114(5):1144-54.,1616 Yousef AA, Aborahama AM. The preventive value of epidural calcitonin in patients with lower limb amputation. Pain Med. 2017;18(9):1745-51.. The protocol that used calcitonin showed significant results in reducing the frequency of SP1616 Yousef AA, Aborahama AM. The preventive value of epidural calcitonin in patients with lower limb amputation. Pain Med. 2017;18(9):1745-51..

For the treatment of pain, in general, there is evidence of the efficacy and benefits of the drugs and the epidural administration used in the studies analyzed in this review. Bupivacaine blocks the voltage-gated sodium channels, stabilizes the neural membrane, and decreases the nerve impulses. Depending on the dose, it can have a local anesthetic or analgesic effect. It can be used during the entire perioperative period and in the treatment of chronic pain2323 Duarte LT, Fernandes Mdo C, Fernandes MJ, Saraiva RA. Continuous epidural analgesia: analysis of efficacy, side effects and risk factors. Rev Bras Anestesiol. 2004;54(3):371-90.,2424 Deer TR, Serafini M, Buchser E, Ferrante FM, Hassenbusch SJ. Intrathecal bupivacaine for chronic pain: a review of current knowledge. neuromodulation: technology at the neural interface. Neurom Techonol Neural Interface. 2002;5(4):196-207.. The epidural route is well-established as safe and effective, and also providing synergetic effects with opioids, including fentanyl, also epidurally2424 Deer TR, Serafini M, Buchser E, Ferrante FM, Hassenbusch SJ. Intrathecal bupivacaine for chronic pain: a review of current knowledge. neuromodulation: technology at the neural interface. Neurom Techonol Neural Interface. 2002;5(4):196-207.. Fentanyl is a synthetic opioid, µ-receptor agonist with fast and intense initial analgesic effect, but of short duration. The association of local anesthetics with opioids epidurally has been described as a promoter of better-quality analgesia when compared to its single use, whether epidurally or systemic route in the case of opioids2323 Duarte LT, Fernandes Mdo C, Fernandes MJ, Saraiva RA. Continuous epidural analgesia: analysis of efficacy, side effects and risk factors. Rev Bras Anestesiol. 2004;54(3):371-90.. Calcitonin is a hormone produced by the thyroid gland cells, responsible for regulating the calcium homeostasis. Its effect in controlling pain has been reported for different types of neuropathic pain, including PLP2525 Ito A, Yoshimura M. Mechanisms of the analgesic effect of calcitonin on chronic pain by alteration of receptor or channel expression. Mol Pain. 2017;13:1744806917720316.

26 McCormick Z, Chang-Chien G, Marshall B, Huang M, Harden RN. Phantom limb pain: a systematic neuroanatomical-based review of pharmacologic treatment. Pain Med. 2014;15(2):292-305.
-2727 Jaeger H, Maier C. Calcitonin in phantom limb pain: a double-blind study. Pain. 1992;48(1):21-7..

The prevalence of PLP observed in the studies1515 Karanikolas M, Aretha D, Tsolakis I, Monantera G, Kiekkas P, Papadoulas S, et al. Optimized perioperative analgesia reduces chronic phantom limb pain intensity, prevalence, and frequency: a prospective, randomized, clinical trial. Anesthesiology. 2011;114(5):1144-54.,1616 Yousef AA, Aborahama AM. The preventive value of epidural calcitonin in patients with lower limb amputation. Pain Med. 2017;18(9):1745-51. was remarkably different; in the first, it was less than 10%, and in the second, 100%. In both studies, the cause of amputation was a peripheral vascular disease; however, the second study mentions that all patients had diabetes, which may have contributed to a higher prevalence of PLP since many could have a history of fiber sensory neuropathy. From the perspective of pain control, it is relevant that the first study had preoperative analgesia and that the entire analgesic regime was continuous. In the second study, analgesia was intra and post-operative in a bolus. The data analysis suggests the importance of considering the preoperative analgesia - 48h before the procedure, besides the intra- and post-operative analgesia - since it seems to impact the prevalence of PLP. This observation can guide future studies and can also be considered for the elaboration of clinical procedures.

Concerning non-pharmacological approaches, interventions based on the phantom motor execution and graded motor imagery showed significant results for the treatment of PLP; however, no data was presented for SP, and the analysis showed a risk of bias in the studies1717 Ortiz-Catalan M, Guðmundsdóttir RA, Kristoffersen MB, Zepeda-Echavarria A, Caine-Winterberger K, Kulbacka-Ortiz K, et al. Phantom motor execution facilitated by machine learning and augmented reality as treatment for phantom limb pain: a single group, clinical trial in patients with chronic intractable phantom limb pain. Lancet. 2016;388(10062):2885-94.,1818 Limakatso K, Madden VJ, Manie S, Parker R. The effectiveness of graded motor imagery for reducing phantom limb pain in amputees: a randomised controlled trial. Physiotherapy. 2019;28. S0031-9406(18)30188-3..

The motor execution for the phantom limb proposed in study1717 Ortiz-Catalan M, Guðmundsdóttir RA, Kristoffersen MB, Zepeda-Echavarria A, Caine-Winterberger K, Kulbacka-Ortiz K, et al. Phantom motor execution facilitated by machine learning and augmented reality as treatment for phantom limb pain: a single group, clinical trial in patients with chronic intractable phantom limb pain. Lancet. 2016;388(10062):2885-94. was carried out with the aid of a virtual and augmented reality equipment. The patient is placed in front of a screen, and the camera captures and transmits the actual image to the screen plus the virtual image of the amputated limb. From the recognition of the myoelectric patters of the stump through electrodes, the system predicts and projects the image of the phantom limb in motion. During the sessions, the patients performed movements with different difficulty degrees and played a game where the phantom limb drove a car. This therapy is independent of the contralateral side and can be especially useful for individuals with bilateral amputation. The need for recognizing the myoelectric patterns requires that the patient has a controllable portion of the biceps and triceps, and this is a limitation.

TIMG used several motor imaging strategies, including: right / left trials where members representing patients' amputated limbs were shown and individuals were asked to imagine themselves performing the movements that the image was supposed to be performing; and mirror therapy, in which the patient positioned the stump of the amputated limb behind a mirror and the intact limb reflects his image in the same mirror1818 Limakatso K, Madden VJ, Manie S, Parker R. The effectiveness of graded motor imagery for reducing phantom limb pain in amputees: a randomised controlled trial. Physiotherapy. 2019;28. S0031-9406(18)30188-3..

Maladaptive mechanisms of the central nervous system plasticity, especially the somatosensory and motor cortex, and reduction of the inter-hemispheres connections are closely related with CPAP and PLP2020 Flor H. Maladaptive plasticity, memory for pain and phantom limb pain: review and suggestions for new therapies. Expert Rev Neurother. 2008;8(5):809-18.,2121 Collins KL, Russell HG, Schumacher PJ, Robinson-Freeman KE, O'Connor EC, Gibney KD, et al. A review of current theories and treatments for phantom limb pain. J Clin Invest. 2018;128(6):2168-76.,2828 Coderre T, Katz J, Vaccarino A, Melzack R. Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain. 1993;52(3):259-85.

29 Flor H, Elbert T, Knecht S, Wienbruch C, Pantev C, Birbaumer N, et al. Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation. Nature. 1995;375(6531):482-4.
-3030 Flor H, Nikolajsen L, Staehelin Jensen T. Phantom limb pain: a case of maladaptive CNS plasticity? Nat Rev Neurosci. 2006;7(11):873-81.. Although the mechanisms involved n the phantom motor execution, mirror therapy, motor imagery, and graded motor imagery still need to be better understood, they are certainly based on usual phenomena of the brain plasticity1717 Ortiz-Catalan M, Guðmundsdóttir RA, Kristoffersen MB, Zepeda-Echavarria A, Caine-Winterberger K, Kulbacka-Ortiz K, et al. Phantom motor execution facilitated by machine learning and augmented reality as treatment for phantom limb pain: a single group, clinical trial in patients with chronic intractable phantom limb pain. Lancet. 2016;388(10062):2885-94.,3131 Diers M, Christmann C, Koeppe C, Flor H. Mirrored, imagined and executed movements differentially activate sensorimotor cortex in amputees with and without phantom limb pain. Pain. 2010;149(2):296-304.. Some advantages of these approaches are the relatively low number of undesirable effects - although the transient exacerbation of PLP can occur during the treatment, the low cost, and the patient's independence to perform the exercises in some of them.

Although some patients were also on the pharmacological therapy during the protocols, the benefits of these combined therapies were not investigated, leaving another question for future studies.

CPAP is a complex condition, which mechanisms still require a better understanding. Although SP and PLP are different, especially in terms of sensory alterations clinically detectable by the patient's report and the sensory test of the stump, the pathophysiological mechanisms overlap. The point in common seems to be the afferent hyperexcitability before, during, and after amputation, leading to plastic alteration and reorganization of the peripheral afferents, and also the dorsal root ganglia, spinal dorsal horn, brain stem, thalamus, and cortical structures, as well as the sympathetic activation66 Taylan A, Derya Ö. Chronic post-surgical pain. Agri. 2009;21(1):1-9.,2020 Flor H. Maladaptive plasticity, memory for pain and phantom limb pain: review and suggestions for new therapies. Expert Rev Neurother. 2008;8(5):809-18.,3030 Flor H, Nikolajsen L, Staehelin Jensen T. Phantom limb pain: a case of maladaptive CNS plasticity? Nat Rev Neurosci. 2006;7(11):873-81.. Therefore, the benefits found in this review, both for the pharmacological and non-pharmacological treatments, which mechanisms were addressed above, can be ultimately explained by the action in different levels of the organization of the sensory pathways, preventing or reverting the alterations in response to amputation. Following this line of thought, the pharmacological approaches that promote the reduction in peripheral and spinal excitability in the perioperative period have the benefit to prevent such alterations and reorganization of the sensory system in the maladaptive sense. The therapies to treat PLP analyzed in this review have a known impact on the cortical reorganization that occurred due to amputation, contributing to its reversion.

STUDY LIMITATIONS

Amputation is a situation of high vulnerability to individuals. In addition, some of the procedures are carried in urgent or emergency situations. The combination of these facts contributes to making it difficult to perform and conduct studies, influencing the sample size, randomization, blinding, outcome measures, and other variables that impact the higher risk of bias found in half of the studies of this review.

For review purposes, the sample of this study is a limitation. The time established for the search may have influenced since there are studies in the reference lists found in the exploratory search that are cited in the literature and are previous to the established timeframe, especially after the nineties, suggesting its importance and shortage of studies. The methodology of the studies may also have impacted since 22 articles were excluded because they did not meet the inclusion criteria for being a case study or case series. Another limitation was that no studies on CPAP were found, whether pharmacological with gabapentin, pregabalin, anticonvulsants, memantine, and NMDA agonists2323 Duarte LT, Fernandes Mdo C, Fernandes MJ, Saraiva RA. Continuous epidural analgesia: analysis of efficacy, side effects and risk factors. Rev Bras Anestesiol. 2004;54(3):371-90., or non-pharmacological such as transcutaneous electrical nerve stimulation, vibration therapy, acupuncture, hypnosis, biofeedback, electroconvulsive therapy, cognitive-behavioral approach, physiotherapy, manipulation, ultrasound, repetitive transcranial magnetic stimulation, spinal stimulation, and cryoneurolysis2222 Bach S, Noreng MF, Tjhllden NU. Phantom limb pain in amputees during the first 12 months following limb amputation, after preoperative lumbar epidural blockade. Pain. 1988;33(3):297-301.,2323 Duarte LT, Fernandes Mdo C, Fernandes MJ, Saraiva RA. Continuous epidural analgesia: analysis of efficacy, side effects and risk factors. Rev Bras Anestesiol. 2004;54(3):371-90.,3232 Nikolajsen L, Jensen TS. Phantom limb pain. Br J Anaesth. 2001;87(1):107-16.,3333 Yaputra F, Widyadharma E. Management of phantom limb pain: a review. Int J Med Rev Case Reports. 2018;5:29-32..

CONCLUSION

From the analysis of the studies included in this review, it is possible to suggest a protective effect of preventive pharmacological therapies for CPAP, administered epidurally, in combination with bupivacaine and fentanyl or the first two added to calcitonin, in the perioperative regime. Although the risk of individual bias in the studies was low, further studies are recommended in order to strengthen the evidence. For non-pharmacological therapies to control CPAP, phantom motor execution and gradual motor images, although there are promising data with the prospect of positively impacting the lives of individuals, greater caution is necessary in view of the risk of uncertain bias and high risk of observed bias. Although the set of data presented is promising, caution is necessary since it was not possible to quantitatively analyze the findings of this review. The data presented in this study can be useful to assist in the establishment or reinforce conducts already adopted in care protocols and in the conduct of new studies responding to the gaps that remain.

  • Sponsoring sources: none.

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Publication Dates

  • Publication in this collection
    08 Jan 2021
  • Date of issue
    Oct-Dec 2020

History

  • Received
    03 Feb 2020
  • Accepted
    21 July 2020
Sociedade Brasileira para o Estudo da Dor Av. Conselheiro Rodrigues Alves, 937 Cj2 - Vila Mariana, CEP: 04014-012, São Paulo, SP - Brasil, Telefones: , (55) 11 5904-2881/3959 - São Paulo - SP - Brazil
E-mail: dor@dor.org.br