Pharmakologische Interventionen zur Behandlung von Phantomschmerzen
Referencias
References to studies included in this review
References to studies excluded from this review
References to studies awaiting assessment
Additional references
Characteristics of studies
Characteristics of included studies [ordered by study ID]
| Study characteristics | ||
| Methods | Controlled clinical trial; DB followed by open phase, 3‐period, cross‐over; no wash‐out period; non‐involved doctor prepared drugs and order of administration Ff‐up after 10 days of each treatment period (DB phase) | |
| Participants | Severe phantom pain for at least 1 month despite extensive pain therapy; majority of upper and lower extremity amputations of cancer aetiology, rest due to vascular and trauma; 10 participants, 5 males; mean age in yrs (SD): 50 (14); duration of phantom pain, months: 4.8 | |
| Interventions |
| |
| Outcomes | Number of participants with ≥ 50% pain relief on subjective pain intensity score 0 to 100; Feeling of well‐being from 0 to 100; Sedation score from 0 to 100; Adverse events; Dropouts/withdrawals | |
| Notes | Limitations related to dosing and small sample size; n = 10 | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Low risk | Physician not involved in study prepared batches of medications and order of administration |
| Blinding (performance bias and detection bias) | Low risk | Identical capsules; outcomes assessed at the medical centre acute pain service |
| Blinding of outcome assessment (detection bias) | Unclear risk | Outcomes assessed at the medical centre acute pain service but not clear if blinded |
| Incomplete outcome data (attrition bias) | Low risk | Complete outcome data for all |
| Selective reporting (reporting bias) | Unclear risk | Results in the DB phase reported in graphical form noting level of significance but without numerical results; the results for the specified outcomes in the methods section of the published study were reported, although not necessarily as our preferred outcomes |
| Other bias | High risk | no wash‐out period; carry‐over effect not addressed |
| Size of study | High risk | n = 10 |
| Study characteristics | ||
| Methods | Randomised, DB, cross‐over; 6 weeks each treatment arm; 1 week wash‐out period; computer‐generated randomisation Ff‐up at 6 wks | |
| Participants | Phantom pain of at least 6 months with pain intensity of at least 40 mm on 100‐millimetre VAS scale; majority with lower limb amputations; time since amputation is 18 months; 19 participants, 15 males; mean age, yrs (SD): 56.25 (17.5); baseline mean pain intensity (SD) (converted and presented in cm VAS by Bone 2002 study authors): treatment group 6.1 (1.8); placebo 6.7 (1.9) | |
| Interventions |
| |
| Outcomes | Change in pain intensity 100‐millimetre VAS at end of treatment week 6 vs baseline (converted and presented in cm VAS by Bone 2002 study authors); Mean pain intensity difference at end of treatment week 6; Categorical phantom pain intensity (0 = none, 1 = mild pain, 2 = moderate pain, 3 = severe pain) end of treatment to baseline; Change in mood on HADS; Change in function on BI; Change in sleep on SIS; Number of rescue tablets; Adverse events; Dropouts/withdrawals | |
| Notes | For lifestyle indices, sample size may be too small to rule out type 2 error; used between‐group analysis for comparisons; n = 19 | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomisation |
| Allocation concealment (selection bias) | Low risk | Organized remotely (hospital pharmacist) |
| Blinding (performance bias and detection bias) | Low risk | "identical coded medication bottles containing identical tablets of gabapentin and placebo" |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not described who assessed and if blinded |
| Incomplete outcome data (attrition bias) | Low risk | "Data from these 19 patients were included in the results presented, using intention‐to‐treat analysis" |
| Selective reporting (reporting bias) | Low risk | All specified outcomes in methods section of published study were reported, although not necessarily as our preferred outcomes |
| Other bias | Low risk | (+) wash‐out period; baseline VAS pain score before placebo/gabapentin not significantly different |
| Size of study | High risk | n = 19 |
| Study characteristics | ||
| Methods | Randomised, DB, cross‐over with 72‐hour wash‐off period; computer‐generated randomisation Ff‐up at 60 min after injection | |
| Participants | PLP of at least 6 months, lower extremity amputation of traumatic and vascular aetiology; 8 participants, 6 males; mean age, yrs (SD): 70.1 (7.7); baseline pain intensity on VAS from 0 no pain to 10 worst pain ever experienced, mean (SD): 7.9 (0.8) treatment group; 7.6 (0.7) control group | |
| Interventions |
| |
| Outcomes | Pain intensity on VAS from 0 no pain to 10 worst pain ever experienced; Mean difference pain intensity; Adverse events; Dropouts/withdrawals; Other outcomes: phantom sensation, mirror displacement in healthy limbs | |
| Notes | Small number of participants; n = 8; preliminary results | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomisation (confirmed through email correspondence with author) |
| Allocation concealment (selection bias) | Low risk | "saline or local anaesthetic solutions prepared in a separate room by a nurse" |
| Blinding (performance bias and detection bias) | Low risk | "Syringes of same size; an independent physician blinded to contents of syringe performed injections" |
| Blinding of outcome assessment (detection bias) | Low risk | "The same physician who performed the basal clinical examination blinded to the treatment, visited the patients collecting number of painful muscle areas present within 1 hr of injection. The intensity of the phantom pain was evaluated before and after treatment by means of the VAS from 0 (no pain) to 10 (worst pain)" |
| Incomplete outcome data (attrition bias) | Low risk | All participants accounted for |
| Selective reporting (reporting bias) | Low risk | All specified outcomes in methods section of published study were reported, although not necessarily as our preferred outcomes |
| Other bias | Low risk | (+) wash‐out period; baseline pain intensity during anaesthetic and saline not significantly different |
| Size of study | High risk | n = 8 |
| Study characteristics | ||
| Methods | Randomised, DB, cross‐over, 1 hr each treatment arm; time between infusions 48 hours; Randomisation by drawing lots by person not involved in study Ff‐up at 30, 60 min, 48 hrs after infusion | |
| Participants | Chronic phantom pain > 6 months' duration; upper and lower extremity amputation of vascular, traumatic, cancer, chronic pain in aetiologies, mean pain intensity ≥ 3 on 10‐centimetre VAS scale; 20 participants; 15 males; median age, yrs (range): 57 (19.3 to 72.7); mean baseline pain intensity on 10‐centimetre VAS: 4.32; duration of phantom pain, yrs: 12.41 | |
| Interventions |
| |
| Outcomes | Number of participants with ≥ 50% pain reduction on 10‐centimetre VAS; Change in pain intensity on 10‐centimetre VAS; Adverse events: Dropouts/withdrawals; Other outcomes: basal sensory assessments | |
| Notes | Relatively small sample size; n = 20; wide range in duration of phantom pain; ketamine alone was given to only 10 participants | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Drawing of lots |
| Allocation concealment (selection bias) | Low risk | Person not involved in study randomised and prepared solutions |
| Blinding (performance bias and detection bias) | Unclear risk | "neither investigator performing experiment nor the patients were aware of the solutions infused" "In some cases, drug‐related side effects occurred which rendered blinding of physician performing the tests and patients questionable" |
| Blinding of outcome assessment (detection bias) | Unclear risk | "In some cases, drug‐related side effects occurred which rendered blinding of physician performing the tests and patients questionable" |
| Incomplete outcome data (attrition bias) | Unclear risk | Missing outcome data in 1 group, but not related to outcome |
| Selective reporting (reporting bias) | Low risk | All specified outcomes in methods section of published study were reported, although not necessarily as our preferred outcomes |
| Other bias | Unclear risk | Carry‐over effect |
| Size of study | High risk | n = 20 |
| Study characteristics | ||
| Methods | Randomised, cross‐over, 4‐week double‐blinded phase with 1 to 2 weeks' wash‐out period; a long‐term open phase for responders to intervention; physician with no contact with participants randomised and kept code Ff‐up: hourly for pain and adverse event; weekly during 4 weeks of DB phase; long term 6, 12 mos (open) | |
| Participants | Phantom pain at least 3 in 10‐centimetre VAS; with upper and lower extremity amputations; 12 participants, 10 males; mean age, yrs (SD): 50.58 (14.01); mean baseline pain intensity on 10‐centimetre VAS (SD): 4.65 (1.06); time since amputation, years (SD): 16.49 (14.01) | |
| Interventions |
| |
| Outcomes | Change in pain intensity on 0‐to‐10‐centimetre VAS; Number of participants with pain reduction of > 50% (10‐centimetre VAS); Change in mood/depression on Self‐Rating Depression Scale; Long‐term outcomes (6 months, 12 months): only with morphine sulfate; n = 9 Other outcomes: pain‐related self‐assessment scale; active coping and catastrophising using West Haven‐Yale Multidimensional Pain Inventory; Brief Stress Scale; psychophysical thresholds, 2‐point discrimination; attentional performance with d2 Test of Attention, magnetoencephalography | |
| Notes | Small sample size (n = 12); cortical reorganisation results based on 3 participants (open phase) | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Low risk | Physician with no contact with participants randomised and kept code. |
| Blinding (performance bias and detection bias) | Unclear risk | Described as a double‐blind study; efforts were made to blind participants (e.g. treatment and placebo preparations were "put into exactly identical pills by the pharmacy"; identical treatment phases). The authors of the study acknowledged in their discussion that the participants were able to guess the morphine medication (but not the placebo) due to side effects, but there was no mention of feedback as to the correctness of their guess. Also, pain reduction scores with the morphine treatment were not significantly correlated with participant‐assessed treatment expectancy outcomes. |
| Blinding of outcome assessment (detection bias) | Unclear risk | Described as double‐blind study; while there was mention of psychologist (not involved in giving treatment to the participant) who administered psychological assessment scales, it was unclear who assessed pain intensity and side effects |
| Incomplete outcome data (attrition bias) | Low risk | All participants accounted for in analysis of outcomes |
| Selective reporting (reporting bias) | Low risk | All specified outcomes in methods section of published study were reported, although not necessarily as our preferred outcomes. |
| Other bias | Low risk | (+) wash‐out period |
| Size of study | High risk | n = 12 |
| Study characteristics | ||
| Methods | Controlled clinical trial, cross‐over; 2‐hour wash‐out period; double‐blind phase, then an open phase with the intervention (s‐calcitonin) for longer‐term assessment; drawing of lots by person not involved in study Ff‐up: short‐term: 24 hrs before and after treatment (double‐blind); long‐term: 6 mos, 1 to 2 yrs (open phase) | |
| Participants | Phantom pain 0 to 7 days following amputation; all except one are lower limb amputations of vascular, traumatic, malignancy, and infectious aetiology, at least 3 on 0‐to‐10 numerical analogue scale; 21 participants, 12 males; median age yrs (range): 59 (20 to 78) | |
| Interventions |
| |
| Outcomes | Change in pain intensity on 0‐to‐10 numerical analogue scale; Number of participants with pain reduction of > 50%; Long term (at 1 yr): number of participants with reduction of > 75%; Adverse events; Dropouts/withdrawals; Other outcomes: number of phantom pain attacks, number of participants requiring second infusion for phantom pain recurrence | |
| Notes | n = 21 | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | "patients with PLP exceeding 3 on NAS were randomly divided into 2 groups" |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding (performance bias and detection bias) | Low risk | "double‐blind" |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not described |
| Incomplete outcome data (attrition bias) | Unclear risk | Some missing data, as some participants did not have the second infusion, placebo, as their NAS did not exceed 3 |
| Selective reporting (reporting bias) | Unclear risk | Numerical results for pain intensity on NAS not reported, although out in graphical form and noted significance; all specified outcomes in methods were reported, although not necessarily our preferred outcomes |
| Other bias | Unclear risk | Unclear if baseline pain characteristics were not significantly different in treatment and placebo interventions |
| Size of study | High risk | n = 21 |
| Study characteristics | ||
| Methods | Randomised, DB, parallel; computer‐generated randomisation Ff‐up at end of 3 wks | |
| Participants | History of PLP of at least 12 months; PLP of at least 4 on 11‐point numeric rating scale; majority of upper and lower extremity amputations of traumatic aetiology; 36 participants, 29 males; median age in years (range): 62 (28 to 76) in memantine group; 61 (35 to 77) placebo; baseline average pain intensity on 11‐point numeric rating scale (SD): 5.1 (2.13) in memantine group; 5.2 (2.02) placebo | |
| Interventions |
| |
| Outcomes | Change in pain intensity on 11‐point numeric rating scale; Number of participants with > 50% mean pain reduction on 11‐point numeric rating scale; NNTB for 50% pain reduction (95% CI); Change in mood/depression score on German validated depression scale; Change in PDI; Adverse events; Dropouts/withdrawals | |
| Notes | Low‐powered study; dosage too low, however this is the limit of clinical tolerability as seen in studies; n = 36 | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomisation |
| Allocation concealment (selection bias) | Low risk | Doctor not involved in study prepared randomisation; medications prepared in hospital pharmacy |
| Blinding (performance bias and detection bias) | Low risk | Placebo and memantine (treatment intervention) had the same colour and size (5 mg/capsule) |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not described |
| Incomplete outcome data (attrition bias) | Unclear risk | Last observation carried forward |
| Selective reporting (reporting bias) | Low risk | All specified outcomes in methods section of published study were reported, although not necessarily as our preferred outcomes |
| Other bias | Unclear risk | Baseline characteristics, e.g. time since amputation, dissimilar; longer time period since amputation in the memantine group, but the duration of phantom pain comparable |
| Size of study | High risk | n = 36 |
| Study characteristics | ||
| Methods | Controlled clinical trial, DB, cross‐over; 3‐day wash‐out period; non‐involved doctor prepared sealed, numbered envelope for each participant containing order of drugs Ff‐up at end of infusion: 45 min | |
| Participants | Postamputation stump and phantom pain; upper and lower extremity amputation mostly malignancy in aetiology, rest trauma and infection, reflex dystrophy; 11 participants, 8 male; mean age, yrs (range): 47 (32 to 78); baseline pain intensity on 100‐millimetre VAS: 30.2; median duration of phantom pain, yrs (range): 4 (0.75 to 14) | |
| Interventions |
| |
| Outcomes | Change in pain intensity on 0‐to‐100‐millimetre VAS; Adverse events; Dropouts/withdrawals; Other outcomes: McGill Pain Questionnaire, pressure pain threshold, wind‐up‐like pain, thermal stimulus response, temporal summation of heat‐induced pain, reaction time | |
| Notes | Small sample size; n = 11 | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Low risk | "doctor not involved in study prepared, sealed and numbered envelope for each patient containing order of ketamine and saline administration" |
| Blinding (performance bias and detection bias) | Low risk | Double‐blind design; ketamine and saline same form (IV) and amount; probably done |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not described |
| Incomplete outcome data (attrition bias) | Low risk | All participants were analysed as to outcomes |
| Selective reporting (reporting bias) | Unclear risk | Numerical results for pain intensity in VAS not reported but presented in graph as % of baseline values and noted significance; all specified outcomes in methods section of published study were reported, although not necessarily as our preferred outcomes |
| Other bias | Low risk | (+) wash‐out period; baseline pain characteristics basically similar in treatment and control periods |
| Size of study | High risk | n = 11 |
| Study characteristics | ||
| Methods | Randomised, DB, parallel; randomisation by central pharmacy Ff‐up at 6 wks | |
| Participants | PLP or residual limb pain; upper and lower limb amputation of vascular, traumatic, cancer, infectious aetiologies; amputation at least 6 months, pain at least 3 months, at least 2 on 0‐to‐10 numerical rating scale; 39 participants, 17 males; mean age, yrs (SD): 44.4 (9.4) in amitriptyline group; 45.3 (13.3) in control; time since amputation, yrs (SD): 11.3 (10.9) in amitriptyline; 10.6 (9.1) control; baseline mean pain intensity on 0‐to‐10 NRS (SD): 3.6 (2.4) amitriptyline; 3.1 (2.6) in control | |
| Interventions |
| |
| Outcomes | Mean change in pain intensity on 0‐to‐10 NRS; Change in mood/depression on CES‐D; Change in function on FIM; Change in QOL/handicap on CHART; Adverse events; Dropouts/withdrawals; Other outcomes: MPQ, Modified Brief Pain Inventory, satisfaction | |
| Notes | Sample represents only 18% of eligible and may have only selected those refractory to standard treatment; n = 39 | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomised by pharmacy investigational drug service; probably appropriate random sequence generation |
| Allocation concealment (selection bias) | Low risk | Random assignment and preparation of medication by hospital pharmacy |
| Blinding (performance bias and detection bias) | Low risk | "a 7 day supply of medication provided to each participant each week in identical gelatin capsules in plastic holder so that study personnel and participants were blind to medication assignment" |
| Blinding of outcome assessment (detection bias) | Low risk | "all pre and post treatments measures were administered by research assistant blinded to the subject assignment" |
| Incomplete outcome data (attrition bias) | Unclear risk | Not all randomised participants were included in analysis (2 (10%) in amitriptyline group excluded) |
| Selective reporting (reporting bias) | Low risk | All specified outcomes in methods section of published study were reported, although not necessarily as our preferred outcomes |
| Other bias | Low risk | Similar baseline characteristics between 2 groups (see characteristics of population above) |
| Size of study | High risk | n = 39 |
| Study characteristics | ||
| Methods | Randomised, DB, parallel, computer‐generated randomisation by doctor not involved in study Ff‐up at end of treatment at 21 days | |
| Participants | Chronic PLP of at least 12 months; traumatic upper limb amputations; 16 participants, 14 males; median age 62 (35 to 71) | |
| Interventions |
| |
| Outcomes | Pain intensity; Dropouts/withdrawals; Other outcomes: intracortical inhibition; intracortical facilitation | |
| Notes | Small number of participants; n = 16 | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomisation |
| Allocation concealment (selection bias) | Low risk | Doctor not involved in study performed randomisation; hospital pharmacy prepared medication |
| Blinding (performance bias and detection bias) | Low risk | "the study medication was produced in hospital pharmacy using capsules of same colour and size for placebo and memantine" |
| Blinding of outcome assessment (detection bias) | Low risk | The investigator who undertook the TMS and data analysis was blinded to participants' treatment allocation and assessed pain intensity at same time |
| Incomplete outcome data (attrition bias) | Unclear risk | 1 participant in memantine group who did not continue with drug due to adverse events was excluded from study and not included in analysis |
| Selective reporting (reporting bias) | Low risk | All specified outcomes in methods section of published study were reported, although not necessarily as our preferred outcomes |
| Other bias | Low risk | Baseline characteristics between 2 groups similar |
| Size of study | High risk | n = 16 |
| Study characteristics | ||
| Methods | Randomised, DB, cross‐over; 6 weeks each treatment arm; wash‐out period of 5 weeks; computer‐generated randomisation Ff‐up at 6 wks | |
| Participants | PLP and residual limb pain, with upper and lower extremity amputations of vascular, traumatic, cancer, infectious aetiology; time since amputation at least 6 months; with average pain intensity of at least 3 on 0‐to‐10 numerical rating scale; 24 participants, 18 males; mean age, yrs (SD): 52.1 (15.5); baseline mean pain intensity on 0‐to‐10 numerical rating scale (SD): 4.38 (2.57) | |
| Interventions |
| |
| Outcomes | Mean change in pain intensity on 0‐to‐10 NRS; Mean change in mood/depression on CES‐D; Change in function on FIM; Change in QOL/handicap on CHART; Adverse events; Satisfaction; Other outcomes: participant rating of global improvement; Modified Brief Pain Inventory; SF‐MPQ sensory score; SF‐MPQ affective score | |
| Notes | Underpowered study; n = 24 | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated random numbers |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding (performance bias and detection bias) | Low risk | "pharmacy compounded gabapentin and placebo capsules that were identical in appearance so that study investigators and participants could not determine study assignment by the capsules" |
| Blinding of outcome assessment (detection bias) | Low risk | Research study nurse contacted each participant to assess pain intensity; probably done |
| Incomplete outcome data (attrition bias) | Unclear risk | Not all randomised participants were included in final analysis |
| Selective reporting (reporting bias) | Unclear risk | Adverse events not described in detail/not specified; withdrawals and dropouts not described |
| Other bias | Low risk | (+) wash‐out period; within‐subject analysis |
| Size of study | High risk | n = 24 |
| Study characteristics | ||
| Methods | Randomised, DB, cross‐over, 4 weeks each treatment arm; 2‐week wash‐out phase; randomisation by central pharmacy Ff‐up at end of treatment at 30 days | |
| Participants | Chronic PLP; all upper extremity amputations of traumatic aetiology; 8 participants, 7 males; mean age in years (SD): 45 (12.51); baseline pain intensity on 0‐to‐100 VAS endpoints (SD): 46.98 (20.38) | |
| Interventions |
| |
| Outcomes | Change in pain intensity on 0‐to‐100 VAS endpoints; Pain in residual limb; Adverse events; Dropouts/withdrawals; Other outcomes: magnetoencephalography recording | |
| Notes | Small sample size; n = 8 | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | "the order of treatment was randomised" but not described |
| Allocation concealment (selection bias) | Low risk | "scientist not involved in study kept a record of treatment assignment" |
| Blinding (performance bias and detection bias) | Low risk | Member of central pharmacy provided the blinded tablets; placebo substance of identical appearance following same dosage scheme |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not described |
| Incomplete outcome data (attrition bias) | Low risk | All participants accounted for in analysis |
| Selective reporting (reporting bias) | Low risk | All specified outcomes in methods section of published study were reported, although not necessarily as our preferred outcomes |
| Other bias | Low risk | (+) wash‐out period |
| Size of study | High risk | n = 8 |
| Study characteristics | ||
| Methods | Randomised, DB, 40 minutes each treatment arm; cross‐over with interval of 24 hours for each infusion; block randomisation Ff‐up at 30 min after end of infusion | |
| Participants | Persistent postamputation pains > 6 months, lower and upper extremity amputations; 31 participants, 19 males; mean age, yrs (SD): 54 (13); time since amputation in months (SD): 81 (87.4) | |
| Interventions |
| |
| Outcomes | Pain intensity on computerised 0‐to‐100 VAS; Subjective self reported % pain relief on 0%‐to‐100% numeric scale; NNTB for 30% PLP pain reduction (95% CI); Treatment satisfaction scores on 0‐to‐100 numeric scale; Adverse events; Dropouts/withdrawals; Other outcomes: sedation scores | |
| Notes | Study has a power of 80%; carry‐over effects possible, but baseline pain scores in both groups similar as well as short duration of action of drugs; n = 31 | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Block randomisation |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding (performance bias and detection bias) | Low risk | All study medications were identical in appearance; investigator administering study medication blinded from intervention; participant and research co‐ordinator blinded |
| Blinding of outcome assessment (detection bias) | Low risk | "during the infusion, the investigator administering the study medication was blinded from the outcome assessment (pain and sedation) and the subject and research coordinators were blinded to the exact timing of study medication administration" |
| Incomplete outcome data (attrition bias) | Low risk | 1 participant dropped out from study due to absence of pain before start of infusion and was not included in analysis |
| Selective reporting (reporting bias) | Unclear risk | Actual numerical VAS values for pain intensity not reported but presented in graph form and noted significance; all specified outcomes in methods section of published study were reported, although not necessarily as our preferred outcomes |
| Other bias | Low risk | Carry‐over effects addressed and discussed; relatively short duration of action of study medications, use of good active placebo, and baseline pain and sedation scores did not differ significantly between 3 days of infusion |
| Size of study | High risk | n = 31 |
| Study characteristics | ||
| Methods | Randomised, DB, pilot, parallel sequence; 1 group receiving BoNT/A injections and another group receiving combination lidocaine and methylprednisolone injections; “one physician was chosen to implement the treatment protocol for all patients after randomisation.” Ff‐up at 1, 2, 3 ,4 ,5,6 mos | |
| Participants | Adult lower extremity amputees with PLP or RLP, or both with VAS > 5/10 and unresponsive to conventional treatment | |
| Interventions |
| |
| Outcomes | Pain intensity by 0‐to‐10 VAS; Changes in pressure pain tolerance; Dropouts/withdrawals | |
| Notes | Study has a small size; n = 14 | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | Technique of allocation not clearly described |
| Blinding (performance bias and detection bias) | Low risk | Participants were blinded to the type of treatment they received; medications same in appearance, dosage amount, and route |
| Blinding of outcome assessment (detection bias) | Low risk | Evaluators were blinded to the type of treatment participants received |
| Incomplete outcome data (attrition bias) | Unclear risk | The study described the dropouts and withdrawals during the course of the study, but unclear whether these were included in the analysis |
| Selective reporting (reporting bias) | Low risk | All specified outcomes in methods section of published study were reported, although not necessarily as our preferred outcomes |
| Other bias | Unclear risk | Uncertain if baseline characteristics similar in both groups |
| Size of study | High risk | n = 14 (but only an initial report) |
BI: Barthel Index; BoNT/A: botulinum toxin A; CES‐D: Center for Epidemiologic Studies Depression Scale; CHART: Craig Handicap Assessment and Reporting Technique; CI: confidence interval; DB: double‐blind; FIM: Functional Independence Measure; ff‐up: follow‐up; HADS: Hospital Anxiety and Depression Scale; ICF: intracortical facilitation; ICI: intracortical inhibition; IU: international unit; IV: intravenous; max: maximum; mos: months; MPQ: McGill Pain Questionnaire; n: number of participants; NNTB: number needed to treat for an additional beneficial outcome; NAS: numerical analogue scale; NRS: numerical rating scale; PDI: Pain Disability Index; PLP: phantom limb pain; RLP: residual limb pain; QOL: quality of life; SD: standard deviation; SF‐MPQ: Short‐Form McGill Pain Questionnaire; SIS: Sleep Interference Scale; TMS: transcranial magnetic stimulation; VAS: visual analogue scale; wks: weeks; yrs: years.
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
| Sample size of 3 | |
| Not reported as randomised or quasi‐randomised; no mention of treatment allocation; no description of double‐blinding | |
| Not established PLP/pre‐emptive therapy | |
| Not randomised | |
| Not established PLP | |
| Population composed of participants with stump pain; none had PLP | |
| Pre‐emptive/preventative therapy | |
| Sample size of 3 | |
| Case series | |
| Not established PLP but stump pain | |
| Mixed group of phantom pain and causalgias; no control | |
| Case series | |
| Pre‐emptive therapy | |
| Non‐randomised, open study | |
| Pre‐post study; no control group | |
| Case series | |
| Editorial and preventive therapy protocol | |
| Comment on a study done in 2011 | |
| Case report | |
| Pre‐emptive therapy | |
| Mixed diagnoses for central pain | |
| Pre‐emptive therapy | |
| Case report | |
| Case report | |
| Mixed diagnoses with no separate analyses for PLP | |
| Mixed diagnoses with no separate analyses for PLP | |
| No description of randomisation, allocation, double‐blinding, who assessed outcomes, withdrawals/dropouts | |
| Non‐randomised after day 3, where treatment assignment was changed based on response; not all participants were blinded; numerical results for initial responders (first 3 days) not reported | |
| Included all postamputation pains; did not distinguish PLP from other postamputation pains; no separate analysis for PLP |
PLP: phantom limb pain
Characteristics of studies awaiting classification [ordered by study ID]
| Methods | Randomized, double‐blind, placebo‐controlled crossover study |
| Participants | Amputees with constant postamputation pain. Sample size of 12 (but only 9 were analysed) |
| Interventions | Peripheral nerve block |
| Outcomes | The primary outcome was the difference in absolute change between worst pain intensity, either phantom or stump pain, at baseline and at 30 minutes after lidocaine or saline injection. |
| Notes |
Data and analyses
| 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] |
| Analysis 1.1  Comparison 1: Memantine versus placebo, Outcome 1: Change in pain intensity | ||||
| 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] | |
| Analysis 2.1  Comparison 2: Gabapentin versus placebo, Outcome 1: Change in pain intensity | ||||
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 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
Comparison 2: Gabapentin versus placebo, Outcome 1: Change in pain intensity
| Author, year | Intervention | Treatment duration | Follow‐up | Outcomes | Results | Overall direction of efficacy | Adverse events |
|---|---|---|---|---|---|---|---|
| BoNTs | |||||||
| BoNT/A | |||||||
|
| 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 | |||||||
|
| 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 | |
|
| 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 | |
|
| 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 | |||||||
|
| 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 | |||||||
|
| 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 | |
|
| 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 | |||||||
|
| 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 | |
|
| 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 | |||||||
|
| 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 | |||||||
|
| 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 | |
|
| 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 | |||||||
|
| 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 | |
|
| 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 | |||||||
|
| 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 | |||||||
|
| 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 | |||||||
| 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] |
| 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] | |
