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Intervensi farmakologi untuk merawat sakit anggota maya

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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.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Ubat‐ubatan untuk merawat sakit anggota maya dalam kalangan orang dengan kehilangan anggota

Latar belakang

Orang boleh mengalami sakit pada anggota badan yang hilang, contohnya selepas amputasi anggota. Ini dikenali sebagai sakit anggota maya. Pelbagai ubat telah dicuba sebagai rawatan untuk sakit anggota maya. Adalah tidak pasti sama ada sebarang ubat berikut berkesan: botulinum toksin A, opioid, antagonis reseptor N‐methyl D‐aspartate (NMDA) (contohnya ketamine, memantine, dextromethorphan), antikonvulsan, antidepresan, calcitonin, dan anestetik setempat. Adalah tidak pasti sama ada ubat‐ubatan ini boleh membantu sakit, fungsi, mood, tidur, kualiti hidup, kepuasan rawatan, dan keselamatan (contohnya peristiwa buruk) dalam jangka pendek dan panjang.

Keputusan utama

Bagi kemaskini ulasan ini, kami mengulangi carian untuk kajian klinikal yang relevan pada April 2016. Kami menemui satu kajian baru, termasuk 14 kajian dengan sejumlah 269 peserta. Satu laporan awal yang kecil menunjukkan botulinum toksin A tidak mengurangkan sakit anggota maya berbanding lidokain/methylprednisolone. Morfin, gabapentin, dan ketamin memberi kelegaan sakit jangka pendek berbanding plasebo, tetapi penemuan‐penemuan ini kebanyakannya berdasarkan kajian‐kajian kecil. Keputusan untuk calcitonin (berbanding plasebo; berbanding ketamin) dan anestetik setempat (berbanding plasebo) adalah bervariasi. Kajian‐kajian tersebut sangat berbeza, yang menyukarkan penggabungan keputusan‐keputusan untuk ubat‐ubatan yang berbeza. Kebanyakan kajian tidak melaporkan tidur, kemurungan atau mood, kualiti hidup, kepuasan rawatan, atau bilangan orang yang tidak melengkapkan kajian.

Oleh kerana pergantungan kepada beberapa kajian kecil, keputusan perlu ditafsir dengan berhati‐hati. Tiada cukup maklumat tentang keberkesanan dan keselamatan jangka panjang. Kajian‐kajian besar, berkualiti baik dengan susulan lebih panjang dan hasil yang penting bagi pesakit diperlukan. Kajian yang lebih besar dan lebih baik akan membantu kami membuat kesimpulan yang lebih kukuh tentang pelega sakit terbaik untuk pesakit‐pesakit ini.

Authors' conclusions

Implications for practice

Since the last version of this review, only one new study representing another class of drugs, botulinum neurotoxins, in particular botulinum toxin A (BoNT/A), has been added to this update. However, the results of the BoNT/A study did not substantially change our conclusion that the short‐ and long‐term effectiveness of pharmacologic interventions for phantom limb pain (PLP) remains unclear.

For people with phantom limb pain

The information from the studies included in this update is not sufficient to support any particular medication for established PLP. The short‐ and long‐term effectiveness of BoNT/A, opioids, NMDA receptor antagonists, anticonvulsants, antidepressants, calcitonins, and local anaesthetics for clinically relevant outcomes that include pain, function, mood, sleep, quality of life, satisfaction, and adverse events remains unclear. Morphine, gabapentin, and ketamine demonstrate favourable short‐term analgesic efficacy, with the caveat that these results were mostly based on small studies that varied considerably and also lacked long‐term efficacy and safety outcomes.

For clinicians

The information from the studies included in this update is not sufficient to support any particular medication for established PLP. The short‐ and long‐term effectiveness of BoNT/A, opioids, NMDA receptor antagonists, anticonvulsants, antidepressants, calcitonins, and local anaesthetics for clinically relevant outcomes that include pain, function, mood, sleep, quality of life, satisfaction, and adverse events remains unclear. Morphine, gabapentin, and ketamine demonstrate favourable short‐term analgesic efficacy, with the caveat that these results were mostly based on small studies that varied considerably and also lacked long‐term efficacy and safety outcomes. More data are needed to clarify the direction of efficacy of BoNT/A, calcitonins, dextromethorphan, local anaesthetics, and other types of antidepressants. Larger and more rigorous randomised controlled trials are needed to make stronger recommendations about which medications would be useful for clinical practice.

For policymakers

While the evidence regarding effective treatment in PLP is weak at this stage, pharmacologic interventions such as morphine, gabapentin, ketamine, and amitriptyline are worth considering as treatment given the potential severity of PLP in people with limb loss.   

For funders

While the evidence regarding effective treatment in PLP is weak at this stage, pharmacologic interventions such as morphine, gabapentin, ketamine, and amitriptyline are worth considering as treatment given the potential severity of PLP in people with limb loss.   

Implications for research

The following are research directions that would help in studies on pharmacologic interventions in PLP.

General

More data are needed to clarify the direction of efficacy of BoNT/A, calcitonins, dextromethorphan, anaesthetics, and other types of antidepressants. Larger and more rigorous randomised controlled trials are needed to make stronger recommendations about which medications would be useful for clinical practice.

Design

Larger (e.g. ideally at least 200 participants per treatment arm) and more rigorous randomised controlled trials with longer duration (at least 12 weeks) are needed to make stronger recommendations about which medications would be useful for clinical practice.

Measurement (endpoints)

Assessment of clinically relevant outcomes, including pain, function, mood, sleep, quality of life, satisfaction with treatment, safety and tolerability, and withdrawals from the study, in longer time frames, would be important and helpful.

Others

Evaluation of combination pharmacologic interventions would be worthwhile.

Further investigations of drugs for their effectiveness in people with PLP depending on factors such as PLP chronicity (acute or chronic), patient age, and amputation aetiology (dysvascular, traumatic, or other) are needed. Also, analysis of different sensory profiles (burning pain, sharp pain, stabbing pain, or other) in these patients and response to particular drugs would be useful (pain phenotype).

A register for people with limb loss may be helpful, as this could facilitate research by providing more information about patients such as demographic and clinical characteristics, clinical course, and response to therapy. As such, it could aid in determining evidence‐based therapy for this population's medical problems, including phantom limb pain.

Clinical trials evaluating other anticonvulsants and antidepressants that have been found to be effective in other neuropathic pain states would be beneficial.

Background

Description of the condition

This review is an update of a previously published review entitled 'Pharmacologic interventions for treating phantom limb pain' in the Cochrane Database of Systematic Reviews Issue 12, 2011.

Phantom limb pain is pain that is experienced in the missing limb and is a well‐recognised phenomenon after amputation. It is a major cause of morbidity and has a profound impact on patients’ well‐being, activity, lifestyle, functioning, activity, employment, and quality of life (Darnall 2005; Desmond 2010; Ehde 2000; Ephraim 2005; Hanley 2004; Hanley 2009; Millstein 1985; Nikolajsen 2001; Penn‐Barwell 2011; Pezzin 2000; Robbins 2009; Sherman 1984; Sin 2013; Sinha 2011a; Sinha 2011b; Whyte 2002). Phantom limb pain is present in more than 70% of amputees (Burgoyne 2012; Clark 2013; Ephraim 2005; Hanley 2009; Reiber 2010; Richardson 2006). About 92% of patients experience the onset of phantom pain within a week following amputation (Richardson 2006). In more than 65% of patients, it occurs within the first six months of amputation (Jensen 1985; Richardson 2006). Approximately 39% of patients report severe pain intensity, and 27% complain that it is "extremely bothersome" (Ephraim 2005). Phantom limb pain has been described as aching, cramping, burning, tingling, sharp, shooting, stabbing, mixed burning‐tingling or burning‐cramping (Clark 2013; Ehde 2000; Jensen 1983).        

The aetiology and pathogenesis of phantom limb pain is complex and not well understood, although there is agreement that peripheral and central mechanisms are involved. A cascade of changes at several levels of the nervous system occur, from the transected afferent fibres that exhibit spontaneous and abnormal evoked activity to the heightened activity in spinal dorsal horn and then to more central relays in the thalamus and cortex. Processes such as central sensitisation, cortical reorganisation, neuroplasticity, and gray matter changes are implicated (Bolognini 2013; Elbert 2004; Flor 1995; Giummarra 2011; Jensen 2000; Montoya 1998; Moseley 2012; Preißler 2013; Woolf 2011). Phantom limb pain is often considered neuropathic pain because of the changes that involve the central and peripheral nervous systems. 

Description of the intervention

Unfortunately, the optimal treatment for phantom limb pain is far from satisfactory and remains a challenge to this day, as the pathomechanism is still unclear. The rationale for the use of various pharmacologic agents lies in the multifactorial theorised origins of phantom pain, chronic and neuropathic pain, as well as the awareness of the affective, cognitive, and biologic triggers of phantom limb pain and chronic pain.  Pharmacologic interventions that have been studied in the treatment of phantom limb pain include beta‐blockers, calcitonins, anticonvulsants, antidepressants, selective serotonin‐reuptake inhibitors (SSRIs), anaesthetics, opioids, tramadol, analgesics, N‐methyl D‐aspartate (NMDA) receptor antagonists, non‐steroidal anti‐inflammatory drugs (NSAIDs), muscle relaxants, nerve blocks, synthetic cannabinoids, and botulinum neurotoxins (BoNTs).

Why it is important to do this review

There are currently no standard guidelines in the pharmacologic management of phantom limb pain, and therefore a review of all available literature is warranted.

Objectives

This review aimed to summarise the evidence of effectiveness of pharmacologic interventions in treating phantom limb pain.

Methods

Criteria for considering studies for this review

Types of studies

We considered randomised and quasi‐randomised studies on pharmacologic agents for treating phantom limb pain (PLP) compared with placebo, another active treatment, or no treatment. We excluded studies with sample sizes of 5 or less. We also excluded short abstracts from conferences or meetings with inadequate or no reporting of data.

Types of participants

We included studies that involved participants of any age with established PLP. We excluded studies in which participants had stump pain or residual limb pain alone, or postamputation pain that was not phantom pain, or where phantom pain was mixed with other neuropathic pains. We also excluded studies in which participants with phantom pain were mixed with participants with other postamputation pains if no separate or subgroup analyses were reported for phantom pain.

Types of interventions

Pharmacologic agents given singly or in combination, in any dose, by any route were eligible. Preoperative, pre‐emptive, intraoperative, and perioperative pharmacologic interventions undertaken to prevent PLP were not eligible.

Types of outcome measures

Primary outcomes

The primary outcome was change in pain intensity on any standard scale.

Secondary outcomes

  1. Sleep: changes in sleep as measured on any standard sleep scale.

  2. Depression or mood: changes in depression or mood scores as measured on any standard depression or mood scale.

  3. Function: changes in function as measured on any standard function scale.

  4. Quality of life: changes in quality of life scores as measured on any standard quality of life scale.

  5. Adverse events.

  6. Satisfaction with treatment.

  7. Withdrawals from the study.

We considered short‐term (less than or equal to 3 months) and long‐term (more than 3 months) outcomes.

Search methods for identification of studies

Electronic searches

For this update we identified studies for inclusion by searching:

  • The Cochrane Central Register of Controlled Trials (CENTRAL), via the Cochrane Library, Issue 3 of 12, 2016 (Cochrane Register of Studies Online) (12 April 2016);

  • MEDLINE (OVID): September 2011 to March Week 5 2016 (12 April 2016);

  • Embase (OVID): September 2011 to 2016 Week 15 (12 April 2016).

See Appendix 1, Appendix 2, and Appendix 3 for the search strategies used.

For the original review we also searched the Cochrane Pain, Palliative and Supportive Care Review Group (PaPaS) Trials Register, but as it is no longer regularly updated it was not searched for this update. There were no language restrictions.

Searching other resources

We sought additional studies from the following clinical trials registries:

  • ISRCTN registry (controlled‐trials.com) (14 April 2016);

  • ClinicalTrials.gov (clinicaltrials.gov) (14 April 2016);

  • World Health Organization International Clinical Trials Registry Platform (who.int/trialsearch/) (14 April 2016).

We also searched reference lists of retrieved papers.

Data collection and analysis

Selection of studies

Initially, we (MJA,TAH, MD) independently reviewed the titles and abstracts of all the articles identified by the literature search for relevance to the research question. From the titles and abstracts, we assessed if the study satisfied the inclusion criteria regarding the design, participants, diagnosis, and interventions. We then retrieved the full text of relevant titles and abstracts, and the non‐English language articles were translated. Next, we independently performed a final selection of the studies to be included in the review using a predesigned study eligibility form. We resolved any disagreements by discussion. For clarifications and missing information, we contacted authors of the selected studies.

Data extraction and management

We (MJA, TAH) independently extracted the data from the studies that satisfied the inclusion criteria and quality standards. Data extraction included study name; design; sample size; study duration (including follow‐up period); participant characteristics (demographic and clinical); intervention including dosage, route, and treatment duration; comparator or control interventions; short‐ and long‐term outcome measures; secondary outcome measures; number of participants analysed and dropouts/withdrawals in the different treatment groups; and duration of follow‐up. We extracted data onto a specially designed data extraction form. We resolved differences in data interpretation between review authors through discussion.

Assessment of risk of bias in included studies

We (MJA, TAH, MD) independently assessed risk of bias for each included study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions with regard to random sequence generation (selection bias), allocation concealment (selection bias), blinding (performance bias and detection bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other types of biases (Higgins 2011).

  • Random sequence generation (selection bias): We assessed the methods used to generate random sequence and graded the risk as follows: low (e.g. computer‐generated random numbers, table of random numbers); unclear (method not clearly stated).

  • Allocation concealment (selection bias): We assessed the methods used to implement the sequence. Proper allocation sequence concealment gives the assurance that treatments or interventions were allocated without knowing the intervention assignments ahead of time. We graded the risk as follows: low (e.g. use of a third party; use of consecutively numbered, opaque envelopes); unclear (method not clearly stated).

  • Blinding (performance bias and detection bias): We assessed the methods used in blinding the participants and evaluators from knowing which intervention was received. We graded the risk as follows: low (e.g. placebo not distinguishable from treatment in colour, dosage, smell, route; evaluators not the same as those who administered the intervention); unclear (method not clearly stated); high (e.g. no blinding; treatment and placebo are distinguishable in colour, dosage, smell, route; outcome assessors are the same as the treating physician or those who administered the intervention). We excluded studies that were not double‐blind.

  • Blinding of outcome assessment (detection bias): We assessed methods used in blinding evaluators in outcome assessment. We graded the risk as follows: low (e.g. described as blinded; evaluators not the same as those administering intervention); unclear (method not clearly described or stated); high (e.g. no blinding; outcome assessors are the same as the treating physician or those who administered intervention).

  • Incomplete outcome data (attrition bias): We assessed the methods used to handle incomplete outcome data. We graded the risk as follows: low (e.g. all participants accounted for in the analysis; intention‐to‐treat analysis; less than 10% did not complete study); unclear (method not clearly stated; 'last observation carried forward' analysis); high (exclusion of participants, e.g. those who failed to follow up in the final analysis).

  • Selective reporting (reporting bias): We graded the risk as follows: low (results for outcomes intended to be assessed as per methods in the full article or publication are reported); unclear (missing outcomes; results not reported or described for outcomes intended to be assessed as per methods in the full article or publication).

  • Other types of biases (such as carry‐over effect in cross‐over design, baseline characteristics): For carry‐over effect in cross‐over design, we assessed studies as being at low risk when efforts were made to minimise carry‐over effect (e.g. adequate wash‐out period); or high risk (e.g. no wash‐out period; baseline or starting clinical characteristics, such as pain intensity, are significantly different with each intervention); or unclear (strategies are not described).

  • Size of study (checking for possible biases confounded by small size): We assessed studies as being at low risk of bias (i.e. 200 participants or more per treatment arm); unclear risk of bias (50 to 199 participants per treatment arm); or high risk of bias (fewer than 50 participants per treatment arm).

Measures of treatment effect

We initially intended to analyse continuous outcomes using mean differences (MD) in the outcome measures with standard deviations (SDs) to quantify the effects of the pharmacologic intervention (change in pain intensity, sleep, mood, depression, function, quality of life, satisfaction); and dichotomous outcomes using risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNTB) for 50% pain relief. However, due to the extensive variation in the outcomes/outcome measures, analyses, follow‐ups, study designs, interventions, and the reporting of results in the 14 studies included in the review, pooling of the results into a fully satisfactory meta‐analysis was not possible. For some outcomes in a few studies, we combined results where possible.

Unit of analysis issues

We incurred a unit of analysis error for combining the results of some cross‐over studies (Maier 2003; Wiech 2004), which we acknowledged in the Discussion. For the mentioned studies, we considered all measurements from treatment (memantine) periods and all measurements from control periods and analysed as if the trial was a parallel‐group study of treatment versus control. With this approach, the number of observations in the analysis did not correspond to the number of 'units' (participants) that were randomised. In these cross‐over studies (Maier 2003; Wiech 2004), a participant underwent more than one intervention (treatment and control), and therefore there is not just one but two measurements for each outcome from each participant analysed. There was thus doubling of the sample size in the analysis. However, as the studies combined using this approach were underweighted, this unit of analysis error may be regarded as less serious than other types of unit of analysis error (Higgins 2011).

Dealing with missing data

We encountered missing data for some cross‐over studies that we were attempting to combine. For example, in the case of the gabapentin studies (Bone 2002; Smith 2005), standard errors (for treatment effects) were not reported. We performed imputations to enable pooling of results of these studies in a meta‐analysis.

Assessment of heterogeneity

We also initially intended to assess the amount of statistical heterogeneity among the studies by computing the I2 statistic. However, this was not possible for all studies and outcomes due to the differences in the methods as well as in the reporting and presenting of outcomes and results that could not be combined and analysed. We therefore assessed clinical heterogeneity by making qualitative comparisons in terms of the populations, interventions, outcomes/outcome measures, and methods.

Assessment of reporting biases

We did not perform assessment of publication bias because tests are unreliable. Excluding non‐published studies ‐ particularly those with negative results ‐ may overestimate treatment effects, which we acknowledged in the Discussion.

Data synthesis

Due to the extensive variation in the outcomes/outcome measures, analyses, follow‐ups, study designs, interventions, and reporting of the results in the 14 included studies, pooling of the results into a fully satisfactory meta‐analysis was not possible. We primarily prepared a qualitative description or narrative summary of the results. We grouped the studies by drug class, namely botulinum neurotoxins, NMDA receptor antagonists, anticonvulsants, antidepressants, calcitonins, opioids, and local anaesthetics. For a few studies, we combined results of outcomes where possible.

Subgroup analysis and investigation of heterogeneity

We did not perform subgroup analysis, as there were only a few studies included, with one to two studies per drug class. Furthermore, the differences in the methods and analyses, and reporting and presenting of outcomes and results precluded performance of subclass analyses.

Sensitivity analysis

We planned no sensitivity analysis because the evidence base was known to be too small to permit reliable analysis.

Results

Description of studies

Results of the search

We included 14 studies with a total of 269 participants in this update. The original version of the review identified 13 studies from 583 titles and abstracts from electronic database searches. For this update, we identified 348 titles and abstracts from the new searches. After initial screening, we excluded 335, as these were irrelevant to the research question, case series, non‐pharmacologic, preventive, preoperative and pre‐emptive, protocols and ongoing trials, reviews, descriptions of programs and interventions for phantom pain, comments, letters, editorials, conference abstracts, and conference proceedings. We selected eight potentially eligible studies for further scrutiny. We performed the final selection using a predesigned study eligibility form, which resulted in one eligible study. Figure 1 shows the results of the search. Figure 2 and Figure 3 show the 'Risk of bias' graph and summary, respectively.


Study flow diagram.

Study flow diagram.


Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.


Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Included studies

We included 14 studies in this update (Abraham 2003; Bone 2002; Casale 2009; Eichenberger 2008; Huse 2001; Jaeger 1992; Maier 2003; Nikolajsen 1996; Robinson 2004; Schwenkreis 2003; Smith 2005; Wiech 2004; Wu 2002; Wu 2012). We added only one study to the original group of studies reviewed (Wu 2012). We included another class of drugs, botulinum neurotoxins, in particular botulinum toxin A (BoNT/A), to the six classes of drugs previously reviewed, namely, NMDA receptor antagonists, opioids, anticonvulsants, antidepressants, calcitonins, and local anaesthetics.

Ten studies were cross‐over sequences (Abraham 2003; Bone 2002; Casale 2009; Eichenberger 2008; Huse 2001; Jaeger 1992; Nikolajsen 1996; Smith 2005; Wiech 2004; Wu 2002), and four were parallel, including the newly identified study (Maier 2003; Robinson 2004; Schwenkreis 2003; Wu 2012). Eleven studies compared the intervention with placebo alone (Abraham 2003; Bone 2002; Casale 2009; Huse 2001; Jaeger 1992; Maier 2003; Nikolajsen 1996; Robinson 2004; Schwenkreis 2003; Smith 2005; Wiech 2004). Three studies had more than two treatment arms (Abraham 2003; Eichenberger 2008; Wu 2002). The newly identified study looked at BoNT/A injections (Wu 2012). Eight studies examined oral medications (Abraham 2003; Bone 2002; Huse 2001; Maier 2003; Robinson 2004; Schwenkreis 2003; Smith 2005; Wiech 2004); four studies investigated intravenous drugs (Eichenberger 2008; Jaeger 1992; Nikolajsen 1996; Wu 2002); and one examined myofascial injections (Casale 2009).

All studies measured pain relief. Four studies assessed change in function or disability (Bone 2002; Maier 2003; Robinson 2004; Smith 2005). Five studies examined change in mood or depression scores (Bone 2002; Huse 2001; Maier 2003; Robinson 2004; Smith 2005). One study looked at change in sleep quality (Bone 2002). One study measured treatment satisfaction (Wu 2002). Assessment points following application of interventions in the double‐blind phase ranged from 30 minutes to 6 months. See Characteristics of included studies.

A total of 269 participants were included in this updated review, with ages ranging from 19 to 81 years. The number of participants per study ranged from 8 to 36. The reasons for the amputations were traumatic, vascular, neoplastic, infectious, and chronic pain syndromes (reflex sympathetic dystrophy). Of these, trauma was most common. The time since amputation varied from within a week to 57 years, while the duration of PLP ranged from less than a week to 49 years. The baseline pain intensity varied from mild to severe.

Excluded studies

For this update, we excluded seven studies for the following reasons: one was preventative or pre‐emptive therapy (Karanikolas 2011); one was a case series (Licina 2013); one was not randomised (Cohen 2011); one was an editorial for a preventative protocol (Lirk 2012); one was a comment (Neil 2012); one had a sample size of 3 (Ilfeld 2013); and one involved people with mixed neuropathic pain diagnoses without separate analyses for PLP (Van Seventer 2010). See Characteristics of excluded studies.

Risk of bias in included studies

Sequence generation, blinding of outcome assessment, and completeness of outcome data were most often inadequately reported. Another important source of bias in the review was the small size of studies. See Characteristics of included studies. Overall, we considered 10 studies to be at low risk of bias and 4 to be at unclear risk of bias. See review authors' judgement of 'Risk of bias' items (Figure 2) and 'Risk of bias' summary for each study (Figure 3).

Allocation

Eight studies described the method of random sequence generation (Bone 2002; Casale 2009; Eichenberger 2008; Maier 2003; Robinson 2004; Schwenkreis 2003; Smith 2005; Wu 2002), and we judged them to be at low risk of bias. The remaining studies did not report the method of random sequence generation, and we judged them to be at unclear risk of bias. Ten studies described the method of treatment allocation (low risk of bias) (Abraham 2003; Bone 2002; Casale 2009; Eichenberger 2008; Huse 2001; Maier 2003; Nikolajsen 1996; Robinson 2004; Schwenkreis 2003; Wiech 2004), while the remainder of the studies were unclear about their method (unclear risk of bias).

Blinding

We judged 12 studies to be at low risk for blinding (performance bias) (Abraham 2003; Bone 2002; Casale 2009; Jaeger 1992; Maier 2003; Nikolajsen 1996; Robinson 2004; Schwenkreis 2003; Smith 2005; Wiech 2004; Wu 2002; Wu 2012). We judged two studies to be at unclear risk (Eichenberger 2008; Huse 2001). We judged six studies to be at low risk for blinding outcome assessment (Casale 2009; Robinson 2004; Schwenkreis 2003; Smith 2005; Wu 2002; Wu 2012), while the remainder had an unclear risk (Abraham 2003; Bone 2002; Eichenberger 2008; Huse 2001; Jaeger 1992; Maier 2003; Nikolajsen 1996; Wiech 2004).

Incomplete outcome data

We judged seven studies to be at low risk for attrition bias (Abraham 2003; Bone 2002; Casale 2009; Huse 2001; Nikolajsen 1996; Wiech 2004; Wu 2002), while the remaining studies had an unclear risk (Eichenberger 2008; Jaeger 1992; Maier 2003; Robinson 2004; Schwenkreis 2003; Smith 2005; Wu 2012).

Selective reporting

We judged nine studies to have a low risk of reporting bias (Bone 2002; Casale 2009; Eichenberger 2008; Huse 2001; Maier 2003; Robinson 2004; Schwenkreis 2003; Wiech 2004; Wu 2012), while the remaining studies had an unclear risk (Abraham 2003; Jaeger 1992; Nikolajsen 1996; Smith 2005; Wu 2002).

Other potential sources of bias

We judged one study to have a high risk of bias for carry‐over effect due to lack of a wash‐out period (Abraham 2003). Three studies had an unclear risk (Jaeger 1992; Maier 2003; Wu 2012), as the baseline characteristics of the intervention groups were not similar.

Size of study

All studies had small sample size (fewer than 50 participants per treatment arm), so we judged them to be at high risk of bias.

Effects of interventions

Table 1 contains a summary of the results for the effects of interventions. Analysis 1.1 and Analysis 2.1 show results for the outcome change in pain intensity for memantine and gabapentin, respectively.

Open in table viewer
Table 1. Summary of results

Author, year

Intervention

Treatment

duration

Follow‐up

Outcomes

Results

Overall direction of efficacy

Adverse events

BoNTs

BoNT/A

Wu 2012

  1. BoNT/A, 1 mL = 50 units for each injection site

  2. combi l/m, 1 mL = 0.75 mL of 1% lidocaine and 0.25 mL methylprednisolone 40 mg/mL for each painful site

1 tx episode

At 1, 2, 3, 4, 5, 6 mos

Change in VAS, change in pressure pain tolerance

No significant change in phantom pain and pressure pain tolerance

Not described

NMDA antagonists

Memantine

Maier 2003

  1. memantine 30 mg/d; oral

  2. placebo

3 weeks

At end of

3 weeks

Pain intensity 11‐point NRS; number of participants with > 50% pain reduction; NNTB;

mood; disability; adverse events

No sig diff in change in pain level, in number of

participants with > 50% pain relief; depression scores; disability indices

in 2 grps; overall number severe events higher in

memantine grp

Vertigo,

tiredness,

headache,

nausea,

restlessness,

excitation,

cramps

Wiech 2004

  1. memantine titrated up to 30 mg/d; oral

  2. placebo

4 weeks

each

treatment

arm

At end

of 4

weeks

of each

arm

Pain intensity 0‐to‐100 VAS; MEG recording; adverse events

No sig diff in change in pain

intensity, cortical

reorganisation in both grps

Nausea,

fatigue,

dizziness,

agitation,

headaches

Schwenkreis 2003

  1. memantine titrated up to 30 mg/d; oral

  2. placebo

3 weeks

At end of

3 weeks

Pain intensity 11‐point NRS; ICI; ICF

No sig diff in pain intensity;

enhanced ICI; reduced ICF

Not

described

Dextromethorphan

Abraham 2003

  1. dextromethorphan 120 mg/d; oral

  2. dextromethorphan 180 mg/d; oral

  3. placebo

10 days

each

treatment

arm 

At end of

10 days of

each arm

Number of participants with ≥ 50% pain relief; feeling of well‐being; sedation score; adverse events

Dextromethorphan grps with ≥ 50% pain relief; with sig better feeling of well‐being scores; with sig lower sedation scores

+

None

reported

Ketamine

Nikolajsen 1996

  1. ketamine 0.5 mg/kg once, IV infusion

  2. placebo

45 min

each

treatment

arm

At end of IV infusion

Pain intensity 0‐to‐100‐millimetre VAS; adverse events; McGill; pressure pain threshold; wind‐up like pain; thermal stimulus response; temporal

summation of heat‐induced pain; reaction time

Sig dec in pain intensity; in

pain evoked by mechanical

stimulation; inc in pressure

pain threshold; no alteration in temperature sensitivity in

ketamine group

+

Insobriety,

discomfort,

elevation of

mood

Eichenberger 2008

  1. ketamine 0.4 mg/kg once, IV infusion

  2. calcitonin 200 IU, once, IV infusion

  3. combination ketamine/calcitonin, IV

  4. placebo

1 hour

each

arm

At 30, 60

mins, 48

hours after

infusion

Pain intensity; number of participants with ≥ 50% pain reduction on 10‐centimetre VAS; basal sensory assessment; adverse events

Sig dec pain intensity in

ketamine alone and combination vs placebo and calcitonin; sig inc in number of responders in ketamine alone and combination vs placebo and calcitonin; sig

inc in electrical thresholds with

combination treatment but no

change in pressure or heat thresholds

+

Loss of

conscious

ness, light

sedation,

light visual

hallucination,

hearing

impairment,

position/

feeling

impairment

Anticonvulsants

Gabapentin

Bone 2002

  1. gabapentin titrated up to 2400 mg or max tolerable dose; oral

  2. placebo

6 weeks

each arm

Weekly

and at

end of

6 weeks

Pain intensity 100‐millimetre VAS; pain intensity

difference; depression

score (HADS); function (BI); sleep (SIS); no. of rescue tabs; adverse events

Significantly greater pain

intensity diff with gabapentin at end of treatment; no sig diff in depression score, function,

sleep, no. of rescue tablets with the treatments

+a

b

Somnolence, dizziness,

headache,

nausea

Smith 2005

  1. gabapentin titrated up to 3600 mg/d; oral

  2. placebo

6 weeks

At end of 6 weeks of each

arm

Pain intensity 0‐to‐10 NRS;

depression score (CES‐D); function (FIM);

handicap (CHART);

satisfaction; global

improvement rating; pain

inventory; McGill

No sig group diff on any outcomes at end of treatment

c

Not

described

Antidepressants

Amitriptyline

Robinson 2004

  1. amitriptyline 10 mg/d titrated to max of 125 mg/d; oral

  2. benztropine mesylate 0.5 mg/d; oral

6 weeks

At end of 6 weeks

Pain intensity 0‐to‐10 NRS;

depression score (CES‐D); function (FIM); handicap (CHART); pain inventory; McGill; satisfaction

No sig group diff on any outcomes at end of treatment

Dry mouth

(more severe),

dizziness

Calcitonins

Jaeger 1992

  1. s‐calcitonin 200 IU, IV infusion

  2. saline

20‐minute

IV infusion;

once

24 hours

after

infusion

(DB);

7 to 152

days,

weekly

(open

phase)

Pain intensity 0‐to‐10 NAS in open phase/long term; number of participants with > 50%, 75% pain relief; adverse events

Sig dec in median pain intensity with s‐calcitonin at 24

hours after infusion; at 1 yr,

62% of participants with 75% pain

reduction

+

Headache,

vertigo,

nausea,

vomiting,

phantom

sensation,

drowsiness,

hot/cold

flushes

Eichenberger 2008

  1. ketamine 0.4 mg/kg, once, IV infusion

  2. calcitonin 200 IU, once, IV infusion

  3. combination ketamine/calcitonin, IV

  4. placebo

1 hour

each arm

At 30, 60

mins, 48

hours after

infusion

Pain intensity; number of

participants with ≥ 50% pain relief on 10‐centimetre VAS; basal sensory assessments; adverse effects

No sig dec in pain intensity with calcitonin vs placebo at 48 hrs; number of responders

not significantly different from

placebo

Drowsiness,

nausea,

facial

flushing,

hot/cold

flushes,

dizziness

Opioids

Morphine

Huse 2001

  1. Morphine sulfate titrated up to 300 mg/d or max tolerable dose; oral

  2. placebo

4 weeks

each arm

(DB)

End of each

treatment

phase of 4

weeks

Pain intensity 10‐centimetre VAS; number of participants with > 50% pain reduction; depression score; pain‐related self assessment scale;

WHYMPI; BSS; psycho‐

physical thresholds;

2‐point discrimination;

attentional performance;

MEG

Sig pain reduction during morphine; 42% with > 50% pain relief; 8% with 25% to 50% pain relief during morphine; no sig change in perception and

pain thresholds; significantly

lower attentional performance

during morphine; scores on pain experience scale, depression score, WHYMPI, BSS with no sig relationship with pain reduction; 2 of 3 with clear cortical reorganisation

+

Constipation only sig

adverse

effect among

others, e.g.

tiredness,

dizziness,

sweating,

micturition

difficulty,

vertigo,

itching,

respiration

Wu 2002

  1. morphine 0.2 mg/kg, IV infusion

  2. lidocaine 4 mg/kg, IV infusion

  3. placebo (diphenhydramine)

40 mins of IV

infusion

30 mins

after end of infusion

Pain relief 0‐to‐100% numeric scale; NNTB for

30% pain reduction;

satisfaction; sedation

scores; adverse events

Sig dec in phantom and stump pain intensity during IV morphine; NNTB 1.9 (95% CI 1.3 to 3.7); significantly higher satisfaction with morphine; no sig diff in sedation scores

+

Sedation

(but no sig

diff with other groups)

Local anaesthetics

Lidocaine

Wu 2002

  1. morphine 0.2 mg/kg, IV infusion

  2. lidocaine 4 mg/kg, IV infusion

  3. placebo (diphenhydramine)

40 mins

of IV

infusion

30 mins

after end of

infusion

Pain relief 0‐to‐100% numeric scale; NNTB for

30% pain reduction;

satisfaction; sedation

scores; adverse events

No sig dec in PLP vs placebo; NNTB 3.8 (95% CI 1.9 to 16.6); significantly higher satisfaction with lidocaine vs

placebo; no sig diff in sedation scores

Sedation

scores not

significantly

different

from

placebo

Bupivacaine

Casale 2009

  1. bupivacaine 2.5 mg/mL, 1mL, contralateral myofascial injection

  2. placebo (saline)

Injections

given

once

After 1

hour

Pain intensity 0‐to‐10 VAS from 0 no pain to 10 worst pain ever experienced;

pain intensity difference;

phantom sensation;

mirror displacement

in healthy limbs; adverse

effects

Sig pain relief with bupivacaine; reduction in phantom sensation in 6 of 8 participants

+

 None

BI, Barthel Index; BoNT/A, botulinum toxin A; BSS, Brief Stress Scale; CES‐D, Center for Epidemiologic Studies Depression Scale; CHART, Craig Handicap Assessment and Reporting Technique; CI, confidence interval; combo, combination; d, day; DB, double‐blind; dec, decrease; diff, difference; dx, diagnosis; FIM, Functional Independence Measure; grp, group; grps, groups; HADS, Hospital Anxiety and Depression Scale; ICI, intracortical inhibition; ICF, intracortical facilitation; inc, increase; IU, international units; IV, intravenous; l/m, lidocaine/methylprednisolone; max, maximum; MEG, magnetoencephalography; min, minutes; mos, months; NAS, numerical analogue scale; NNTB, number needed to treat for an additional beneficial outcome; NRS, numerical rating scale; PLP, phantom limb pain; sig, significant; SIS, Sleep Interference Scale; tx, treatment; VAS, visual analogue scale; WHYMPI, West Haven‐Yale Multidimensional Pain Inventory; yr, year; apain intensity; bmood, sleep, function; cpain intensity, mood, function, handicap, satisfaction

1. Botulinum neurotoxins (BoNT/A injections)

The newly identified study in this update is a pilot study investigating the effectiveness of BoNT/A injections in PLP or residual limb pain (RLP), or both (Wu 2012). Fourteen participants with PLP or RLP, or both were randomised into two groups to receive either BoNT/A injections or lidocaine/methylprednisolone injections. The intensity of the phantom limb pain was not improved with either BoNT/A (at 1 ml equivalent to 50 units for each injection site) (P = 0.49) or lidocaine/methylprednisolone (1 mL mixture of 0.75 mL lidocaine and 0.25 mL methylprednisolone 40 mg/mL for each painful site) injections (P = 0.42). The outcomes sleep, depression or mood, function, quality of life, adverse events, satisfaction with treatment, and withdrawals from the study were not described or reported.

2. Opioids

Two cross‐over studies investigated the effectiveness of morphine in treating phantom pain (Huse 2001; Wu 2002). One compared oral morphine with placebo (Huse 2001), and the other compared morphine infusion with lidocaine and placebo (Wu 2002).

The pain intensity (mean (SD)) on a 0‐to‐100 visual analogue scale (VAS) was significantly reduced during the oral morphine phase compared with the placebo phase (P = 0.036) at four weeks (3.26 (1.59) versus 3.99 (1.23)). About 42% (5) of participants experienced equal to or greater than 50% pain relief (considered responders in study) with morphine versus one participant in placebo (P < 0.05) (Huse 2001). Significantly lower pain intensity was also seen with intravenous morphine compared to placebo (P < 0.01) in the other study (Wu 2002). Furthermore, subjective, self reported percentage pain relief was significantly higher with morphine. The NNTB for 30% pain relief for morphine in this study was 1.9 (95% confidence interval (CI) 1.3 to 3.7) (Wu 2002).

As for secondary outcomes, scores on self rating depression scale, West Haven‐Yale Multidimensional Pain Inventory, and Brief Stress Scale were not significantly associated with pain reduction (Huse 2001). Treatment satisfaction scores (mean (SD)) were significantly higher in the morphine group compared with placebo (45.9 (35.5) versus 9.6 (21); P < 0.01) (Wu 2002).

Adverse events were classified as moderate and were significantly more frequent with morphine. These were tiredness, dizziness, sweating, constipation, micturition difficulties, nausea, vertigo, itching, and short of respiration, but a difference between treatment and placebo groups was only found for constipation (Huse 2001). One participant dropped out due to absence of pain before the start of treatment (Wu 2002).

The outcomes sleep, function, and quality of life were not described or reported in these studies.

3. NMDA receptor antagonists

Six studies investigated the effectiveness of NMDA receptor antagonists in established PLP: memantine versus placebo (Maier 2003; Schwenkreis 2003; Wiech 2004); dextromethorphan versus placebo (Abraham 2003); ketamine versus placebo (Nikolajsen 1996); and ketamine versus calcitonin, combination ketamine and calcitonin, and placebo (Eichenberger 2008).

Pain intensity was not significantly decreased with 30 mg/day of memantine for three to four weeks in traumatic amputees with chronic pain (Maier 2003; Schwenkreis 2003; Wiech 2004). Combining the results of two memantine studies for the outcome change in pain intensity showed a standardised mean difference (SMD) 0.24 (95% CI ‐0.31 to 0.79) (Maier 2003; Wiech 2004), which is an overall effect of no difference between treatment and control groups (Analysis 1.1). In so doing, however, a unit of analysis error was incurred. The cross‐over study was treated as though it was a parallel study by taking all measurements from memantine periods and all measurements from placebo periods and analysing these data as in a parallel study comparing memantine versus placebo (Wiech 2004).

In the dextromethorphan study, 4 participants on 120 mg dextromethorphan/day and 1 participant on 180 mg/day reported 50% pain relief compared with placebo (P = 0.01) after 10 days of treatment in the double‐blind phase (Abraham 2003).

Ketamine at 0.5 mg/kg given once as intravenous infusion significantly reduced pain intensity in a population of 11 participants with chronic phantom pain that was mostly malignant in aetiology (P < 0.05) compared with placebo. In another study, pain intensity was significantly decreased with ketamine alone at 0.4 mg/kg and combination ketamine‐calcitonin after infusion compared with placebo (P < 0.05) in a group of 20 participants with chronic phantom pain of various aetiologies. Ketamine alone and its combination with calcitonin had significant pain reduction of greater than 50% versus placebo (Eichenberger 2008).

Two studies assessed change in mood (depression scores and feelings of well‐being scores) (Abraham 2003; Maier 2003). One study found no significant difference in the change in depression scale score between memantine and placebo (Maier 2003). On the other hand, the scores of feelings of well‐being were significantly better in the dextromethorphan group compared with placebo (P = 0.025) (Abraham 2003). Only one study assessed change in function or disability, where the pain disability index (recreation, social activity, family and home responsibilities, sexual behaviour, occupation, life support) did not change significantly in either group (Maier 2003).

Severe adverse events such as loss of consciousness and other mild/moderate effects such as light sedation, light visual hallucination, hearing impairment, and position impairment were reported with ketamine in one study (Eichenberger 2008). Insobriety, discomfort, and mood elevation were described in another (Nikolajsen 1996). Adverse effects such as nausea, fatigue/tiredness, dizziness/vertigo, agitation/restlessness, and headaches were observed with memantine (Maier 2003; Wiech 2004). No adverse events were observed in any of the participants during dextromethorphan treatment and at one‐month follow‐up (Abraham 2003). No dropouts or withdrawals were reported in the NMDA antagonists studies, except in one study, where two participants dropped out in the memantine group due to adverse events and three from the placebo group due to insufficient analgesia (Maier 2003) .

The outcomes depression or mood, function, and quality of life were reported in some studies. The outcomes sleep and satisfaction with treatment were not described or reported.

4. Anticonvulsants

Two studies examined the effectiveness of gabapentin in treating phantom pain in placebo‐controlled, cross‐over trials of six weeks' duration (Bone 2002; Smith 2005). In the first study, pain intensity difference on the 100‐millimetre VAS (mean (SD)) (converted and presented as centimetre VAS in Bone 2002) was significantly higher with gabapentin at 2.4 g/day at the end of six weeks compared with placebo in a population of 19 participants with chronic phantom pain (3.2 (2.1) versus 1.6 (0.7), P = 0.03) (Bone 2002). In the second study of 24 participants with chronic phantom and stump pain following amputation of various aetiologies, average phantom pain intensity differences on the0‐to‐10 numerical rating scale (mean (SD)) in the gabapentin phase did not differ significantly from placebo (0.94 (1.98) versus 0.49 (2.20), t = 0.70) (Smith 2005). Combining the results of these two studies using the generic inverse variance method for the outcome change in pain intensity showed a mean difference of ‐1.16 (95% CI ‐1.94 to ‐0.38) (P = 0.004), favouring gabapentin (Analysis 2.1).

Change in mood/depression and function were evaluated using different outcome scales, so the results could not be combined. The end‐of‐treatment median (interquartile range) Hospital Anxiety and Depression Scale, Barthel Index, and Sleep Interference Scale were not significantly different between gabapentin and placebo (12 (4 to 22) versus 14 (5 to 25); 85 (70 to 105) versus 87 (65 to 105); 3 (1 to 5) versus 4 (1 to 5)) (Bone 2002), respectively. Average scores for Center for Epidemiologic Studies Depression Scale (CES‐D) (mean (SD)) were not significantly different between gabapentin and placebo (4.22 (9.20) versus 3.78 (10.13), t = ‐0.11), respectively (Smith 2005). Craig Handicap Assessment and Reporting Technique (CHART) and Satisfaction With Life Scale (SWLS) change scores were not significant (no values shown) (Smith 2005). Somnolence (n = 7), dizziness (n = 2), headache (n = 2), and nausea (n = 1) reported in the gabapentin group were not significantly different from control group (Bone 2002).

The outcomes quality of life and treatment satisfaction were not described or reported in any of the studies.

5. Antidepressants

The only eligible study determined the effectiveness of a 6‐week course of amitriptyline in treating phantom pain (versus an active control of benztropine mesylate) in 39 participants with at least 3 months of phantom or residual limb pain after amputations for various causes (Robinson 2004).

The average PLP on the 0‐to‐10 numerical rating scale (mean (SD)) was not significantly different between the amitriptyline and active placebo groups at the end of 6 weeks (3.1 (2.7) versus 3.1 (2.9)). The CES‐D, Functional Independence Measure, CHART, and SWLS scores (mean (SD)) were not significantly different between amitriptyline and placebo (12.9 (8.5) versus 16.1 (13.1); 74.5 (18.8) versus 79.1 (3.3); 360 (142) versus 417 (75); 21.2 (6.4) versus 21.8 (8.7)), respectively. Mouth dryness, drowsiness, blurred vision, constipation, dizziness, altered sleep, nausea, vomiting, urinary retention, diarrhoea, and tinnitus were reported in the amitriptyline group.

The outcomes sleep, quality of life, and treatment satisfaction were not described or reported.

6. Calcitonins

Two studies examined the effectiveness of s‐calcitonin infusion in treating phantom pain (Eichenberger 2008; Jaeger 1992). One study compared it to saline placebo in a group of 21 participants with severe phantom pain developing within a week after amputations of various aetiologies (Jaeger 1992). Another study compared it to ketamine, combination ketamine and calcitonin, and placebo in 20 participants with chronic phantom pain (Eichenberger 2008).

Median pain intensity on a 0‐to‐10 numerical analogue scale (NAS) was significantly reduced 24 hours after 200 international units (IU) calcitonin infusion (P < 0.001) (Jaeger 1992). Four participants in the group where calcitonin infusion was the first of the matched pair of infusions given (one consisting of calcitonin and the other of saline placebo) did not require a second infusion, as they had a NAS of less than 3. In the other study, pain intensity on the 10‐centimetre VAS did not significantly decrease with 200 IU calcitonin infusion compared with placebo at 48 hours. Also, the number of responders (equal to or greater than 50% pain relief) to calcitonin did not differ significantly from placebo (2 of 20 versus 1 of 19) (Eichenberger 2008).

Both studies described adverse events. With calcitonin, 2 participants had facial flushing, 5 had nausea, 1 had sedation, and 1 had dizziness (Eichenberger 2008). Twelve of 21 participants experienced one or more of the following adverse events: headache (n = 2), vertigo (n = 2), nausea (n = 6), vomiting (n = 5), augmentation of phantom sensation (n = 4), drowsiness (n = 2), and hot/cold flushes (n = 4) (Jaeger 1992). As for withdrawals, no participants withdrew during the double‐blind phase in the two‐arm study (Jaeger 1992). Dropouts were not described in the calcitonin group in the multi‐arm study (Eichenberger 2008).

The outcomes sleep, depression or mood, function, quality of life, and satisfaction with treatment were not described or reported.

7. Local anaesthetics

Two studies examined the effectiveness of local anaesthetics in treating phantom pain. Bupivacaine at 0.25%, 1 mL, as contralateral myofascial injection given once was compared with placebo (0.9% saline) in a randomised cross‐over trial (Casale 2009). Lidocaine at 4 mg/kg given as intravenous infusion over 40 minutes was compared with morphine (intravenous infusion) and placebo (diphenhydramine) (Wu 2002).

Contralateral myofascial injection of bupivacaine given once to 8 participants with chronic phantom pain following amputations of various aetiologies afforded significantly greater pain reduction (VAS from 0 no pain to 10 worst pain ever experienced) (mean (SD)) versus placebo one hour after the injection (‐5.3 (1.4) versus ‐1.5 (1.3), P = 0.003) (Casale 2009). Phantom pain relief with lidocaine was not significantly different from placebo (P > 0.05) in 31 participants with chronic phantom pain (Wu 2002). There were no reported cardiovascular or respiratory problems or any reports of a stinging sensation after the injection (Casale 2009).

The outcomes sleep, depression or mood, function, and quality of life were not described or reported. Only one study reported adverse events.

See Table 1 for a summary of the results.

Discussion

Summary of main results

In this update we added another class of drugs, botulinum neurotoxins, in particular botulinum toxin A (BoNT/A), to the list of pharmacologic interventions for treating established phantom limb pain. However, the results of the lone eligible investigation on BoNT/A did not substantially change the main results of the original version of the review.

Firstly, the short‐ and long‐term effectiveness of most pharmacologic interventions in established PLP remains unresolved for clinically relevant outcomes that include pain, function, mood or depression, sleep, quality of life, satisfaction, and safety. Botulinum toxin A was ineffective in phantom limb pain (based on a pilot study) in both short‐ and long‐term (up to six months) time frames. Of the remaining six drug classes reviewed, only morphine consistently demonstrated short‐term analgesia (based on two studies: n = 12 (Huse 2001); n = 31 (Wu 2002)), although only one study was adequately powered. The various NMDA receptor antagonists had differential efficacy, in that ketamine and dextromethorphan provided pain relief, and memantine did not. Gabapentin was shown to be beneficial with the pooled results, but these results should be interpreted with caution as computations were based on approximations. The studies on calcitonin and local anaesthetics had conflicting results.

Secondly, there was extensive variation in the methods, interventions, outcomes, outcome measures/scales, follow‐ups, data analyses, and reporting and presenting of results. This limited the pooling of results. Clinically relevant outcomes that include function, mood, sleep, quality of life, and satisfaction were missing in the majority of the studies, including the newly identified study.

Overall completeness and applicability of evidence

Botulinum toxin A injections did not lower phantom limb pain intensity assessed monthly for six months. Botulinum neurotoxins comprise a group of nerve‐blocking biologic agents that exert their blocking effect at the neuromuscular junction by preventing the release of acetylcholine (Aoki 2001a; Aoki 2001b). Of the existing seven serotype botulinum toxins, BoNT/A and botulinum toxin B have been studied in amputation‐related complications such as pain, hyperhydrosis, and involuntary movements (Charrow 2008; Jin 2009; Kern 2003; Kern 2004a; Kern 2004b; Kern 2011). The rationale for using BoNT/A in phantom limb pain relates to the peripheral mechanisms contributing to PLP. Phantom limb pain is often associated with neuroma, excessive muscle tightness, and spasm. Botulinum toxin A reduces muscular activity as a result of the neuromuscular blockade (Aoki 2001b; Brin 1997; Silberstein 2001). The negative results of this pilot study, Wu 2012, are not congruent with earlier studies (Jin 2009; Kern 2003; Kern 2004a; Kern 2004b). The authors of the study cited the small sample size, low baseline VAS scores, and the heterogeneous patient population included in the study. As this was only a preliminary study, it is difficult to make a definitive conclusion regarding the effectiveness and clinical applicability of BoNT/A in phantom limb pain.

Both oral and intravenous forms of morphine significantly reduced pain intensity. The percentage of participants responding to oral morphine in Huse 2001 was comparable to that of another study on morphine for postamputation pains (Wu 2008). As for adverse events, reviews on opioids for chronic non‐cancer and neuropathic pain also found constipation, along with nausea, vomiting, dizziness, and drowsiness as the most common and significant adverse events (Furlan 2006; Furlan 2011; McNicol 2013; Moore 2005).

The rationale for the use of opioids in PLP stems from the observed efficacy of these medications in neuropathic pain states. As with neuropathic pain, peripheral and central neural mechanisms have been implicated in the pathogenesis of PLP. Also, reviews investigating the prescription and use of opioids, in Hall 2013, as well as the effectiveness of opioids in neuropathic pain conditions (e.g. diabetic neuropathic pain, postherpetic neuralgia) included evidence from PLP trials, albeit results on their effectiveness including long‐term adverse events in these conditions have not been strong and conclusive (Finnerup 2015; Furlan 2006; Furlan 2011; Kalso 2004; McNicol 2013). The reasons why opioids might work in phantom pain are not well‐understood. Peripherally and at the spinal level, opioids act via presynaptic nerve terminals and postsynaptic neurons involved in pain transmission. Centrally, these drugs may decrease cortical reorganisation, a phenomenon where the topographic representation of lost extremity is shifted to other areas of the cortex and taken over by sensory input from other areas of the body, leading to perceptual remapping following the amputation (Birbaumer 1997; Elbert 1994; Flor 1995; Ramachandran 1992).

The results for the NMDA receptor antagonists as a group were at best equivocal. Blocking the NMDA receptors in the dorsal horn, which play a significant role in central sensitisation, hyperexcitability, and wind‐up phenomenon, can decrease pain manifestations. Among the NMDA receptor antagonists, dextromethorphan and ketamine had short‐term analgesic effects compared with placebo, but these findings were based on underpowered studies. On the other hand, memantine did not have the same positive effects (Maier 2003; Wiech 2004). The issues raised were low drug dosage, short run‐in period, other probable mechanisms that maintain phantom pain aside from the NMDA receptor activation (Maier 2003), time‐dependent effect of memantine on neural transmission via NMDA receptor pain maintenance, and the differential affinity of the various NMDA receptor antagonists (Wiech 2004).

The differences in the results for ketamine and memantine are not easily explained. Firstly, the type of neuropathic pain involved could be a factor. Ketamine significantly decreased pain evoked by mechanical stimulation and increased pressure pain thresholds (Nikolajsen 1996). Conversely, memantine in neuropathic pain after amputation, surgery, and postherpetic neuralgia neither decreased mechanical and cold allodynia, mechanical hyperalgesia, and wind‐up‐like pain nor increased thresholds to mechanical pressure (Eisenberg 1998; Nikolajsen 2000). However, in the included memantine studies, the detailed characteristics of the neuropathic pain were not explicit nor were there outcomes on allodynia, hyperalgesia, wind‐up‐like pain and pressure pain thresholds. Secondly, the timing of the intervention might be important. Memantine given in combination with brachial plexus blockade in the early postoperative stage significantly decreased the intensity and prevalence of PLP at four weeks and six months (Schley 2007). On the other hand, memantine given in established PLP in the current review led to negative findings. A characteristic of the populations was continuous pre‐existing pain of at least 12 months. Pre‐existing pain results in the formation of a somatosensory “pain memory” that indicates long‐term changes in the central nervous system (Katz 1990). When this pain memory is in place, functional and structural changes in nociceptive structures have already occurred (Lei 2004). NMDA antagonism might thus no longer be useful in longstanding phantom pain where the neuroplastic changes are already fixed. Thirdly, the route of administration might also be an issue. In this review, intravenous ketamine during the chronic phase of phantom pain altered the pain intensity favourably. On the other hand, all three memantine studies used the oral preparation and demonstrated consistent negative findings.

The results for the analgesic efficacy of gabapentin were contradictory. An earlier study, Bone 2002, indicated positive findings in favour of gabapentin, while a later study, Smith 2005, showed otherwise. Combining the results of the two studies entailed estimating certain parameters that include the treatment effect and its standard error (SE) from each study (Bone 2002; Smith 2005). We approximated the SE in one study given the standard deviations of the pain intensity differences and n for treatment and placebo (Bone 2002). In the later study, we computed the SE by dividing the mean difference between placebo and treatment by the given value of the t statistic (Smith 2005). We performed the generic inverse variance method for pooled analysis. The pooled estimate suggested a trend favouring gabapentin, but this should be interpreted with caution for reasons mentioned above. A recent review on gabapentin for chronic neuropathic pain that included PLP found that gabapentin was better than placebo and that 34% to 38% of participants experienced at least 50% pain relief with the drug (Moore 2014). Adverse events were also significantly more frequent with gabapentin in this review (Moore 2014), compared to the Bone study.

The negative results for amitriptyline (based on only one study) were attributed to a missed a small treatment effect, insufficient duration of treatment (six weeks), and the type of participants included (Robinson 2004). Tricyclic antidepressants including amitriptyline have been considered first‐line drugs for neuropathic pain (Finnerup 2015; Moulin 2014; Tan 2010). However, a recent meta‐analysis that focused on amitriptyline in neuropathic pain showed a lack of good‐quality studies to support its beneficial effects or lack of effect (Moore 2015). Furthermore, the review suggested that it may benefit a few and select group of patients, but not the majority (Moore 2015).

The findings on the analgesic action of calcitonin were contrasting. The earlier study involved participants with acute phantom pain (developing within seven days after amputation) (Jaeger 1992), whereas the later study included participants with years of history of phantom pain (Eichenberger 2008). The mechanism involved in the analgesic action of calcitonin is unclear, although its direct central action is likely the main mechanism, as suggested by its inhibitory effect on the neuronal firing in response to peripheral stimulation and the finding of its receptors in the central nervous system structures (Azria 2002). The ineffectiveness of calcitonin in one study was attributed to its possible lack of effect on central sensitisation processes, which are important in phantom pain pathophysiology (Eichenberger 2008).

The results for the local anaesthetics (lidocaine, bupivacaine) were variable. While both are sodium channel blockers, they were administered via different routes. Lidocaine at 4 mg/kg was administered systemically as an infusion, whereas bupivacaine at 2.5 mg was given locally as an injection. Lidocaine infusion was ineffective in PLP, as the mechanisms responsible for PLP are primarily considered to be central, although peripheral inputs are important in maintaining pain. Lidocaine is considered to act for the most part in the periphery by decreasing ectopic discharge following peripheral nerve injury (Wu 2002). Conversely, bupivacaine injection to contralateral myofascial hyperalgesic areas decreased phantom pain intensity (Casale 2009). The mechanism of pain relief from local anaesthetic contralateral injection is not clear. In animal experiments, blocking afferent inputs on the contralateral side can decrease the spontaneous hyperactivity and after discharges following noxious evoked responses in the wide dynamic response neurons in the  ipsilateral (injured) side (Bileviciute‐Ljungara 2001).

Aside from the type of medication, the dosing, route, and ease of administration are also of clinical importance. While some of the drugs were given for a period of days to weeks (oral medications), others were administered as a single dose via relatively more invasive manner (e.g. infusion, injection) such as ketamine, calcitonin, intravenous morphine, and bupivacaine injection. Thus far, outcome assessment, including adverse events, for these single‐dose drugs given intravenously or as injections, have been within short time frames (e.g. at the end of infusion, within 30 minutes to 48 hours). Also, the duration of their analgesic effects has not been documented. This may put some degree of uncertainty on the clinical value of such drugs at this stage for this type of pain, which is generally considered chronic.

Other issues that can impact on applicability of evidence are the characteristics of the population and the phantom limb pain. The majority of studies included populations with mixed amputation aetiologies, although predominantly traumatic. In the United States, dysvascular disease accounts for most amputation cases, followed by trauma (motor vehicular accidents) (Sheehan 2014; Ziegler‐Graham 2008). Also, as aftermath of the Afghanistan and Iraq wars, major limb amputations constitute 7.4% of major limb injuries, and about 88% of these are attributed to explosive device (Stansbury 2008). Phantom limb pain is more likely in traumatic amputees (Ephraim 2005).

Phantom limb pain chronicity (four months to 12 years) was a feature of the included studies, except for one that dealt with acute phantom pain. None of the studies provided analyses that explored the relationship between chronicity and treatment response, although in general, people with chronic pain usually have a more protracted course of treatment, as there are other associated problems such as mood and sleep disorders. Furthermore, none of the studies described the phantom pain in detail (e.g. frequency, quality, mechanism, severity, etc.). The association between characteristics of the phantom limb pain and response to particular drugs needs further investigation.

The second main finding in this review relates to heterogeneity. The study populations varied, from acute PLP to chronic phantom pain, although most were of the chronic type. Seven groups of interventions examining 10 individual drugs of dissimilar doses (e.g. gabapentin at 2.4 g/day or 3.6 g/day; single intravenous morphine infusion), of differing routes (e.g. oral morphine versus morphine infusion; intravenous lidocaine versus myofascial injection of bupivacaine), and of variable duration of administration (minutes versus weeks or months) were studied. A wide range of pain scales and measures were utilised (e.g. 11‐point numerical rating scale, 0‐to‐100 VAS, NNTB for 30% or 50% pain relief, McGill Pain Questionnaire). A variety of scales were used to assess secondary outcomes as well (e.g. Functional Independence Measure or Barthel Index for function; the Hospital Anxiety and Depression Scale or Center for Epidemiologic Studies Depression Scale for depression). Outcomes were measured at different time points ranging from 30 minutes to 6 months. The majority of studies had a cross‐over design that differed in number of treatment arms, phases (blinded and open), and analyses of the data. The results for outcomes were reported and presented in various ways.

Quality of the evidence

Studies were generally small and of short duration. Adequately powered studies yield more accurate and reliable estimates of treatment effect. The clinical applicability of interventions for phantom limb pain that is considered chronic would rely on the assessment of clinically relevant outcomes including adverse events over the long term. Also, the completeness of outcome data was questionable in some studies, as the attrition and exclusions from the analyses were not explicit. Another issue was that the majority of the studies had a cross‐over design, and the possibility of carry‐over effects could not be entirely eliminated. Evaluation of carry‐over effects is not straightforward, as statistical techniques to analyse such effects are far from satisfactory and rely for the most part on judgement (Higgins 2011). To reduce the risk of carry‐over effects, most of the studies utilised sufficient wash‐out periods between treatment periods, except for the dextromethorphan study, which did not report any wash‐out periods. Some studies also reported no significant differences in the baseline pain intensity levels between the start of each treatment period to indicate that carry‐over effect was unlikely.

Potential biases in the review process

This review has several limitations. Firstly, all of the included studies had small sample sizes, which made it problematic to form generalisations and conclusions. Secondly, we did not include studies where populations included participants with a diagnosis of postamputation pains with analyses that did not distinguish PLP from the other pains (e.g. postoperative pain, stump pain, etc.). One study found oral morphine to be more effective than placebo and mexiletine in improving pain but not function in people with postamputation pains (Wu 2008). The exclusion of such a study might have led to an underestimation of the analgesic effect of oral morphine in this review. Also, we did not include a negative study on another class of drugs being investigated for phantom limb pain, synthetic cannabinoids, due to the lack of information regarding methods, data, and actual study results, as it was published only as an abstract (Khanahmadi 2012). Thus, the possibility of publication bias thus cannot be entirely discounted. However, the general results of that study based on the abstract would not have changed the main conclusions of this update. Thirdly, we were not able to do a fully satisfactory meta‐analysis due to the variability in designs, outcomes and outcome measures, and analyses and reporting of the results. For example, for the opioid and anaesthetic studies, different routes of administration were studied. By combining the results of the memantine studies (Maier 2003; Wiech 2004), we incurred a unit of analysis error, as we treated the cross‐over study, Wiech 2004, as though it was a parallel study by taking all measurements from memantine periods and all measurements from placebo periods and analysing these data as in a parallel study. The analysis assumed that this study had 16 participants, when in reality it had only 8. We thus see in the forest plot that the confidence interval is very wide and that the study has very little weight (Analysis 1.1). But to start with, the trial has a very small sample size, so the presentation of forest plot here does not in fact add more to what the individual results show. The strategy of combining the two gabapentin studies was also not without shortcomings (Analysis 2.1). Ideally, the estimates of the treatment effect with their SEs are available in the study, but in this case, they were not; we therefore performed imputations. We noted, however, that the SE estimate of the positive study with the smaller sample, Bone 2002, was slightly smaller, and hence the weight was larger than that of the study with a slightly bigger sample size. It is possible that there was a little more variability in measurement in the other study (Smith 2005). These pooled results should therefore be interpreted with caution.

Agreements and disagreements with other studies or reviews

Several reviews have also identified and discussed various modalities of treatment in phantom pain but without firm recommendations on which is the best for clinical use (Foell 2011; Halbert 2002; Manchikanti 2004; Sherman 1980; Wolff 2011). A recent systematic review identified level 2 evidence (classed as "one or more well‐powered randomized, controlled trials") for the efficacy of intravenous ketamine and intravenous morphine in phantom limb pain in the short term (McCormick 2014). This shows some agreement with the findings of our review.

A recent meta‐analysis on medications for neuropathic pain of various causes including postamputation pain found moderate to strong evidence of efficacy for tricyclic antidepressants, serotonin‐noradrenaline reuptake inhibitors, pregabalin, gabapentin, tramadol, strong opioids, capsaicin patches, and BoNT/A (Finnerup 2015).

Study flow diagram.

Figures and Tables -
Figure 1

Study flow diagram.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figures and Tables -
Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Figures and Tables -
Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Comparison 1: Memantine versus placebo, Outcome 1: Change in pain intensity

Figures and Tables -
Analysis 1.1

Comparison 1: Memantine versus placebo, Outcome 1: Change in pain intensity

Comparison 2: Gabapentin versus placebo, Outcome 1: Change in pain intensity

Figures and Tables -
Analysis 2.1

Comparison 2: Gabapentin versus placebo, Outcome 1: Change in pain intensity

Table 1. Summary of results

Author, year

Intervention

Treatment

duration

Follow‐up

Outcomes

Results

Overall direction of efficacy

Adverse events

BoNTs

BoNT/A

Wu 2012

  1. BoNT/A, 1 mL = 50 units for each injection site

  2. combi l/m, 1 mL = 0.75 mL of 1% lidocaine and 0.25 mL methylprednisolone 40 mg/mL for each painful site

1 tx episode

At 1, 2, 3, 4, 5, 6 mos

Change in VAS, change in pressure pain tolerance

No significant change in phantom pain and pressure pain tolerance

Not described

NMDA antagonists

Memantine

Maier 2003

  1. memantine 30 mg/d; oral

  2. placebo

3 weeks

At end of

3 weeks

Pain intensity 11‐point NRS; number of participants with > 50% pain reduction; NNTB;

mood; disability; adverse events

No sig diff in change in pain level, in number of

participants with > 50% pain relief; depression scores; disability indices

in 2 grps; overall number severe events higher in

memantine grp

Vertigo,

tiredness,

headache,

nausea,

restlessness,

excitation,

cramps

Wiech 2004

  1. memantine titrated up to 30 mg/d; oral

  2. placebo

4 weeks

each

treatment

arm

At end

of 4

weeks

of each

arm

Pain intensity 0‐to‐100 VAS; MEG recording; adverse events

No sig diff in change in pain

intensity, cortical

reorganisation in both grps

Nausea,

fatigue,

dizziness,

agitation,

headaches

Schwenkreis 2003

  1. memantine titrated up to 30 mg/d; oral

  2. placebo

3 weeks

At end of

3 weeks

Pain intensity 11‐point NRS; ICI; ICF

No sig diff in pain intensity;

enhanced ICI; reduced ICF

Not

described

Dextromethorphan

Abraham 2003

  1. dextromethorphan 120 mg/d; oral

  2. dextromethorphan 180 mg/d; oral

  3. placebo

10 days

each

treatment

arm 

At end of

10 days of

each arm

Number of participants with ≥ 50% pain relief; feeling of well‐being; sedation score; adverse events

Dextromethorphan grps with ≥ 50% pain relief; with sig better feeling of well‐being scores; with sig lower sedation scores

+

None

reported

Ketamine

Nikolajsen 1996

  1. ketamine 0.5 mg/kg once, IV infusion

  2. placebo

45 min

each

treatment

arm

At end of IV infusion

Pain intensity 0‐to‐100‐millimetre VAS; adverse events; McGill; pressure pain threshold; wind‐up like pain; thermal stimulus response; temporal

summation of heat‐induced pain; reaction time

Sig dec in pain intensity; in

pain evoked by mechanical

stimulation; inc in pressure

pain threshold; no alteration in temperature sensitivity in

ketamine group

+

Insobriety,

discomfort,

elevation of

mood

Eichenberger 2008

  1. ketamine 0.4 mg/kg once, IV infusion

  2. calcitonin 200 IU, once, IV infusion

  3. combination ketamine/calcitonin, IV

  4. placebo

1 hour

each

arm

At 30, 60

mins, 48

hours after

infusion

Pain intensity; number of participants with ≥ 50% pain reduction on 10‐centimetre VAS; basal sensory assessment; adverse events

Sig dec pain intensity in

ketamine alone and combination vs placebo and calcitonin; sig inc in number of responders in ketamine alone and combination vs placebo and calcitonin; sig

inc in electrical thresholds with

combination treatment but no

change in pressure or heat thresholds

+

Loss of

conscious

ness, light

sedation,

light visual

hallucination,

hearing

impairment,

position/

feeling

impairment

Anticonvulsants

Gabapentin

Bone 2002

  1. gabapentin titrated up to 2400 mg or max tolerable dose; oral

  2. placebo

6 weeks

each arm

Weekly

and at

end of

6 weeks

Pain intensity 100‐millimetre VAS; pain intensity

difference; depression

score (HADS); function (BI); sleep (SIS); no. of rescue tabs; adverse events

Significantly greater pain

intensity diff with gabapentin at end of treatment; no sig diff in depression score, function,

sleep, no. of rescue tablets with the treatments

+a

b

Somnolence, dizziness,

headache,

nausea

Smith 2005

  1. gabapentin titrated up to 3600 mg/d; oral

  2. placebo

6 weeks

At end of 6 weeks of each

arm

Pain intensity 0‐to‐10 NRS;

depression score (CES‐D); function (FIM);

handicap (CHART);

satisfaction; global

improvement rating; pain

inventory; McGill

No sig group diff on any outcomes at end of treatment

c

Not

described

Antidepressants

Amitriptyline

Robinson 2004

  1. amitriptyline 10 mg/d titrated to max of 125 mg/d; oral

  2. benztropine mesylate 0.5 mg/d; oral

6 weeks

At end of 6 weeks

Pain intensity 0‐to‐10 NRS;

depression score (CES‐D); function (FIM); handicap (CHART); pain inventory; McGill; satisfaction

No sig group diff on any outcomes at end of treatment

Dry mouth

(more severe),

dizziness

Calcitonins

Jaeger 1992

  1. s‐calcitonin 200 IU, IV infusion

  2. saline

20‐minute

IV infusion;

once

24 hours

after

infusion

(DB);

7 to 152

days,

weekly

(open

phase)

Pain intensity 0‐to‐10 NAS in open phase/long term; number of participants with > 50%, 75% pain relief; adverse events

Sig dec in median pain intensity with s‐calcitonin at 24

hours after infusion; at 1 yr,

62% of participants with 75% pain

reduction

+

Headache,

vertigo,

nausea,

vomiting,

phantom

sensation,

drowsiness,

hot/cold

flushes

Eichenberger 2008

  1. ketamine 0.4 mg/kg, once, IV infusion

  2. calcitonin 200 IU, once, IV infusion

  3. combination ketamine/calcitonin, IV

  4. placebo

1 hour

each arm

At 30, 60

mins, 48

hours after

infusion

Pain intensity; number of

participants with ≥ 50% pain relief on 10‐centimetre VAS; basal sensory assessments; adverse effects

No sig dec in pain intensity with calcitonin vs placebo at 48 hrs; number of responders

not significantly different from

placebo

Drowsiness,

nausea,

facial

flushing,

hot/cold

flushes,

dizziness

Opioids

Morphine

Huse 2001

  1. Morphine sulfate titrated up to 300 mg/d or max tolerable dose; oral

  2. placebo

4 weeks

each arm

(DB)

End of each

treatment

phase of 4

weeks

Pain intensity 10‐centimetre VAS; number of participants with > 50% pain reduction; depression score; pain‐related self assessment scale;

WHYMPI; BSS; psycho‐

physical thresholds;

2‐point discrimination;

attentional performance;

MEG

Sig pain reduction during morphine; 42% with > 50% pain relief; 8% with 25% to 50% pain relief during morphine; no sig change in perception and

pain thresholds; significantly

lower attentional performance

during morphine; scores on pain experience scale, depression score, WHYMPI, BSS with no sig relationship with pain reduction; 2 of 3 with clear cortical reorganisation

+

Constipation only sig

adverse

effect among

others, e.g.

tiredness,

dizziness,

sweating,

micturition

difficulty,

vertigo,

itching,

respiration

Wu 2002

  1. morphine 0.2 mg/kg, IV infusion

  2. lidocaine 4 mg/kg, IV infusion

  3. placebo (diphenhydramine)

40 mins of IV

infusion

30 mins

after end of infusion

Pain relief 0‐to‐100% numeric scale; NNTB for

30% pain reduction;

satisfaction; sedation

scores; adverse events

Sig dec in phantom and stump pain intensity during IV morphine; NNTB 1.9 (95% CI 1.3 to 3.7); significantly higher satisfaction with morphine; no sig diff in sedation scores

+

Sedation

(but no sig

diff with other groups)

Local anaesthetics

Lidocaine

Wu 2002

  1. morphine 0.2 mg/kg, IV infusion

  2. lidocaine 4 mg/kg, IV infusion

  3. placebo (diphenhydramine)

40 mins

of IV

infusion

30 mins

after end of

infusion

Pain relief 0‐to‐100% numeric scale; NNTB for

30% pain reduction;

satisfaction; sedation

scores; adverse events

No sig dec in PLP vs placebo; NNTB 3.8 (95% CI 1.9 to 16.6); significantly higher satisfaction with lidocaine vs

placebo; no sig diff in sedation scores

Sedation

scores not

significantly

different

from

placebo

Bupivacaine

Casale 2009

  1. bupivacaine 2.5 mg/mL, 1mL, contralateral myofascial injection

  2. placebo (saline)

Injections

given

once

After 1

hour

Pain intensity 0‐to‐10 VAS from 0 no pain to 10 worst pain ever experienced;

pain intensity difference;

phantom sensation;

mirror displacement

in healthy limbs; adverse

effects

Sig pain relief with bupivacaine; reduction in phantom sensation in 6 of 8 participants

+

 None

BI, Barthel Index; BoNT/A, botulinum toxin A; BSS, Brief Stress Scale; CES‐D, Center for Epidemiologic Studies Depression Scale; CHART, Craig Handicap Assessment and Reporting Technique; CI, confidence interval; combo, combination; d, day; DB, double‐blind; dec, decrease; diff, difference; dx, diagnosis; FIM, Functional Independence Measure; grp, group; grps, groups; HADS, Hospital Anxiety and Depression Scale; ICI, intracortical inhibition; ICF, intracortical facilitation; inc, increase; IU, international units; IV, intravenous; l/m, lidocaine/methylprednisolone; max, maximum; MEG, magnetoencephalography; min, minutes; mos, months; NAS, numerical analogue scale; NNTB, number needed to treat for an additional beneficial outcome; NRS, numerical rating scale; PLP, phantom limb pain; sig, significant; SIS, Sleep Interference Scale; tx, treatment; VAS, visual analogue scale; WHYMPI, West Haven‐Yale Multidimensional Pain Inventory; yr, year; apain intensity; bmood, sleep, function; cpain intensity, mood, function, handicap, satisfaction

Figures and Tables -
Table 1. Summary of results
Comparison 1. Memantine versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1.1 Change in pain intensity Show forest plot

2

52

Std. Mean Difference (IV, Fixed, 95% CI)

0.24 [‐0.31, 0.79]

Figures and Tables -
Comparison 1. Memantine versus placebo
Comparison 2. Gabapentin versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

2.1 Change in pain intensity Show forest plot

2

Mean Difference (IV, Fixed, 95% CI)

‐1.16 [‐1.94, ‐0.38]

Figures and Tables -
Comparison 2. Gabapentin versus placebo