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Pharmacotherapy for the prevention of chronic pain after surgery in adults

  1. Luis Enrique Chaparro1,
  2. Shane A Smith2,
  3. R Andrew Moore3,
  4. Philip J Wiffen3,
  5. Ian Gilron4,*

Editorial Group: Cochrane Pain, Palliative and Supportive Care Group

Published Online: 24 JUL 2013

Assessed as up-to-date: 17 JUL 2013

DOI: 10.1002/14651858.CD008307.pub2


How to Cite

Chaparro LE, Smith SA, Moore RA, Wiffen PJ, Gilron I. Pharmacotherapy for the prevention of chronic pain after surgery in adults. Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD008307. DOI: 10.1002/14651858.CD008307.pub2.

Author Information

  1. 1

    Hospital Pablo Tobon Uribe, Anesthesiology Department, Medellin, Colombia

  2. 2

    Queen's University, Department of Anesthesiology & Perioperative Medicine, Kingston, Canada

  3. 3

    University of Oxford, Pain Research and Nuffield Department of Clinical Neurosciences, Oxford, Oxfordshire, UK

  4. 4

    Queen's University, Departments of Anesthesiology & Perioperative Medicine & Biomedical & Molecular Sciences, Kingston, Ontario, Canada

*Ian Gilron, Departments of Anesthesiology & Perioperative Medicine & Biomedical & Molecular Sciences, Queen's University, 76 Stuart Street, Victory 2 Pavillion, Kingston, Ontario, K7L 2V7, Canada. gilroni@queensu.ca.

Publication History

  1. Publication Status: New
  2. Published Online: 24 JUL 2013

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Characteristics of included studies [ordered by study ID]
Amr 2010

MethodsSingle center, randomized, double blind, 3 arms, placebo-controlled trial for 6 months


Participants150 patients scheduled for either partial or radical mastectomy with axillary dissection


InterventionsIn the (Group 1) venlafaxine group, patients received 37.5 mg of venlafaxine extended release along with another capsule (identical in appearance to the gabapentin capsules) once daily at bed time. Patients in the (Group 2) gabapentin group received 300 mg of gabapentin and another capsule (identical in appearance to the venlafaxine extended release capsules) once daily at bed time. Patients in the (Group 3) placebo group received 2 capsules that were filled with thin sugar (1 identical in appearance to the gabapentin capsules and the other identical to venlafaxine extended release capsules) once daily at bed time. Administration of the drugs started the evening before surgery and continued for the first 10 postoperative days, including the day of the surgery.


OutcomesPain scores at rest and movement-induced, morphine consumption, and side effects profile


NotesCo-analgesia: morphine the first 24 hours; acetaminophen + codeine during the rest of the follow-up


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskShuffling envelopes: "A prospective, randomized (sealed envelopes indicate the group of assignment)...

Allocation concealment (selection bias)Low risk"An independent anesthesiologist, who did not participate in the study or data collection, read the number contained in the envelope and made group assignments".

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Control (sugar filled) and/or treatment capsules for each group were packaged in group-specific bottles and coded as Bottle 1, Bottle 2, and Bottle 3 for Groups 1, 2, and 3, respectively. Yellow hard gelatin capsules (identical in appearance to the gabapentin capsules) and gray/peach capsules (identical in appearance to the venlafaxine extended release capsules) were filled with thin sugar. Envelopes, bottles with capsules, and coding were prepared by the pharmacy of the hospital.

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"double-blind design was used, with both patients and postoperative assessors blinded to management protocol"

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe authors reported no missing outcome data

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasLow riskNo other potential sources of bias were detected

Bergeron 2009

MethodsSingle center, randomized, double blind, placebo-controlled trial with long-term follow-up for 6 weeks and one year


Participants18 years or older patients undergoing elective primary total hip arthroplasty using spinal anesthesia to receive either dexamethasone (40 mg intravenous, n = 25) or saline placebo (n = 25)


InterventionsA research collaborator,who did not participate in data collection, prepared an IV infusion bag containing 40 mg of dexamethasone or an equal volume of saline diluted into 40 mL of normal saline according to group allocation. Dexamethasone is colorless and causes no pain when given intravenously.


OutcomesPain Scores, Harris Hip Score


NotesMorphine PCA, acetaminophen and Ibuprofen


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"A research collaborator, who did not participate in data collection, prepared an IV infusion bag containing 40 mg of dexamethasone or an equal volume of saline diluted into 40 mL of normal saline according to group allocation. Dexamethasone is colorless and causes no pain when given intravenously".

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"The patients, anesthesiologists, nurses, and research coordinators gathering the data were blinded to the study arms".

Incomplete outcome data (attrition bias)
All outcomes
Low risk"We lost 10 patients to follow-up for nonmedical reasons due to a large referral network outside our province where patients are routinely followed radiographically and by phone interview".

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgment

Other biasUnclear riskFewer than 50 patients per arm

Brogly 2008

MethodsSingle center, randomized, double-blind, placebo-controlled trial for 6 months


Participants50 patients aged 18-75 yr, ASA I-III, undergoing scheduled total or partial thyroidectomy without lymph node dissection


InterventionsGabapentin 1200 mg PO 2 hours before surgery or matching placebos (placebos are not described)


OutcomesPrimary outcome: analgesic drug consumption was assessed during the procedure and postoperatively in the postanesthesia care unit and after discharge to the ward. Over the first 24 h, pain levels at rest and during swallowing were measured. The day before operation and 6 mo after patients were asked to answer a neuropathic pain diagnostic questionnaire (DN2).


NotesCoanalgesia: Superficial cervical plexus block for all participants. analgesic rescue: paracetamol + tramadol 50 mg


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomization was performed by subgroups of 10 patients with a randomization table".

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot reported

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data (3/50) was minimum

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgment

Other biasHigh riskFewer than 50 patients per arm

Burke 2010

MethodsSingle center, randomized, double-blind, placebo-controlled trial for 3 months


Participants40 ASA physical status I and II patients, aged 18 - 60, with chronic lumbar sacral radiculopathy undergoing elective lumbar discectomy


InterventionsPregabalin 300 mg 2h preoperatively + 150 mg POP at 12 h + 150 mg at 24h


OutcomesPrimary outcome was the change in the present pain intensity (PPI) (visual analog scale [VAS], 0–100 mm [PPI-VAS, McGill Pain Questionnaire]) from preoperatively to 3 months postoperatively


NotesIntraop: paracetamol, morphine, NSAID and SC infiltration of bupivacaine. POP: codeine, acetaminophen and diclofenac


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"In this double-blind study, patients received pregabalin or placebo (sucrose) according to random allocation"

Allocation concealment (selection bias)Low risk"The medication was prescribed according to instructions in a sealed, opaque envelope by an anesthesiologist with no further involvement in the study".

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot reported

Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk"At 3 months postoperatively, patients once again completed the same 6 questionnaires in the presence of the same investigator".

Incomplete outcome data (attrition bias)
All outcomes
Low risk2 patients dropped out from the study, only 

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasHigh riskFewer than 50 patients per arm

Buvanendran 2010

MethodsSingle center, randomized, double-blind, placebo-controlled trial for 6 months


Participants228 patients scheduled to undergo a primary total knee arthroplasty with a diagnosis of osteoarthritis of the operative knee and had the ability to understand and read English


InterventionsPatients randomized to the experimental arm of the study received pregabalin 300 mg orally (per os [PO]), 1–2 h before surgery, 150 mg twice daily for the first 10 postoperative days, 75 mg twice daily on Days 11 and 12, and 50 mg twice daily on Days 13 and 14


OutcomesAdverse events related with the medication, Leeds Assessment of Neuropathic Symptoms and Signs pain scale, knee injury and Osteoarthritis Outcome Score–Physical function Short-form, Range of motion, epidural drug use and postoperative pain assessment


NotesCo-analgesia: epidural Infusion of bupivacaine and fentanyl (PCEA)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Patients were randomized to a treatment group using a computer-generated randomization sequence".

Allocation concealment (selection bias)Low risk"During the study, only the dispensing pharmacist had knowledge of the study codes".

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Control patients received PO-matched placebo tablets, at identical time points, with both pregabalin and placebo capsules provided by Pfizer"

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"The personnel involved with postoperative pain assessments and management of the epidural infusion, physical therapists, and the study patients were blinded to group assignment".

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced across groups

Selective reporting (reporting bias)High riskOutcomes reported are clinically meaningful and validated. However, we detected some discrepancies in the definition of primary and secondary outcome between the published protocol (NCT00558753) and the publication.

Other biasLow riskNo other potential sources of bias were detected

Chan 2011

MethodsMulticenter, randomized, double-blind, controlled trial with long-term follow-up for at least three months


Participants640 patients that were 18 yr or older scheduled, under general anesthesia, for surgery that included a skin incision and that was anticipated to exceed 2 hours, and were expected to be in the hospital for at least 3 days after surgery


InterventionsIntraoperative 70% nitrous oxide


OutcomesThe primary outcome of this follow-up study was chronic postsurgical pain according to the definition by the International Association for the Study of Pain. Secondary outcomes were the impact of chronic postsurgical pain on daily living.


NotesThis study had a very high mortality rate at follow-up (34%)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"….using a computer-generated code, accessed via an automated telephone voice recognition service".

Allocation concealment (selection bias)Low risk"…..automated telephone voice recognition service. Treatment assignment was stratified by site and elective/emergency status of the surgery, using permuted blocks".

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Attending anesthesiologists were required to have knowledge of group identity for the safe administration of anesthesia, but group identity was concealed from the surgeon using drapes or cardboard to screen the anesthesia machine".

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"At the end of the procedure, the intraoperative case report form and documentation of group identity were faxed to the data management center and then placed in an opaque envelope by the anesthesiologist. The envelope was then sealed to ensure blinding of research staff conducting the postoperative follow-ups".

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThis secondary analysis included the Hong Kong population only  

Selective reporting (reporting bias)Low riskOutcomes reported for this secondary analysis are clinically meaningful and validated

Other biasHigh risk"Pain intensity was not described as an outcome in the original 2007 report".

Chaparro 2010

MethodsSingle center, randomized, double-blind, placebo-controlled trial with long-term follow-up for one year


Participants106 patients scheduled to Esthetic Augmentation Mammaplasty were followed one year after the surgery


InterventionsKetamine 25 IV before the beginning of the surgery plus additional 50 mg mixed with the IV anesthetic (2 mg of remifentanil)


OutcomesPain Scores, opioid consumption and adverse effects profile


NotesCoanalgesia: Dipyrone and meperidine. Acetaminophen+Codeine and NSAIDs after discharge


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThrowing coin

Allocation concealment (selection bias)High riskRandomization and allocation in groups of 4 patients. Two patients in a row receiving one treatment will predict the treatment for the next 2

Blinding of participants and personnel (performance bias)
All outcomes
Low riskA registered nurse prepared the bags of saline and ketamine. She did not participated of the outcomes assessment

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes assessors were not aware of the treatment that the patients received

Incomplete outcome data (attrition bias)
All outcomes
High riskSignificant missing outcome data: 53%

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasLow riskNo other potential sources of bias were detected

Clarke 2009

MethodsSingle center, randomized, double-blind, placebo-controlled trial for 6 months


Participants126 Patients 18-75, ASA I, II or III undergoing total hip arthroplasty were eligible


InterventionsPatients were randomly assigned to one of 3 treatment groups (G1: Placebo/Placebo; G2: GBP/Placebo; and G3: Placebo/ GBP). Group 2 received gabapentin 600mg p.o. 2 h before surgery; the other groups received an identical-looking placebo capsule. Upon arrival to the recovery room, group 3 received gabapentin 600mg p.o.; the other groups received an identical-looking placebo capsule.


OutcomesPain scores at rest and movement-evoked; patients were also assessed for the incidence and severity of sedation, nausea, vomiting and pruritus. Patients were administered 3 questionnaires: a follow-up Hip Arthroplasty Pain questionnaire, The Neuropathic Pain Scale and The Hospital Anxiety and Depression Scale. Pain intensity was measured using a 0-10 numeric rating scale (NRS).


NotesPreop: acetaminophen, celecoxib and dexamethasone; POP: acetaminophen, celecoxib and morphine PCA


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"A computer-generated randomization schedule was used to assign patients at random in blocks of 6 to one of the 3 treatment groups".

Allocation concealment (selection bias)Low risk"The schedule was created by the hospital investigational pharmacy, which was otherwise not involved in the clinical care of the patients or in the conduct of the trial. The randomization schedule was kept in the pharmacy and none of the investigators had access to it".

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Gabapentin and placebo medications were encapsulated in identically colored gelatin capsules and packaged in identical individual blister packs by the Sunnybrook Health Sciences Centre Investigational Pharmacy in order to maintain double-blind conditions".

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskIncomplete information

Incomplete outcome data (attrition bias)
All outcomes
High riskMissing outcome data balanced across groups, but > 20%

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasHigh riskFewer than 50 patients per arm

Crousier 2008

MethodsSingle center, randomized, double-blind, placebo-controlled trial with long-term follow-up for 3 months


Participants36 patients, no limit of age, requiring radical mastectomy with axillary dissection


InterventionsKetamine 0.5 mg/kg previous to surgical incision + infusion during surgery at 0.25/mg/kg/h versus saline bolus + infusion


OutcomesPain scores, side effects profile


NotesCo-analgesia: Morphine, acetaminophen/codeine


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskThe method of the sequence generation is not reported

Allocation concealment (selection bias)Unclear riskMethod for allocation concealment is not stated

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskThe method to keep blinded the intervention is not stated

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of the outcomes assessors at 3 months follow-up is unclear

Incomplete outcome data (attrition bias)
All outcomes
High riskThe proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate

Selective reporting (reporting bias)Low riskThe trial was registered and non significant differences with the protocol were noticed

Other biasHigh risk25% (n:3/12) in the ketamine group versus 50% (9/18) in the placebo group, reported presurgical neuropathic pain

De Kock 2001

MethodsSingle center, randomized, double-blind, 5 arms, placebo-controlled trial with long-term follow-up for 3 months


Participants100 Patients aged 55-75 undergoing curative surgical resection of rectal carcinoma


InterventionsControl: saline infusion, Low IV dose: i.v. ketamine at the bolus dose of 0.25 mg/kg followed by an infusion of 0.125 mg/kg per h, High IV dose: 0.5 mg/kg and 0.25 mg/kg per h; Low epi dose: epidural ketamine 0.25 mg/kg and 0.125 mg/kg per h; high Epi dose: 0.5 mg/kg and 0.25 mg/kg per h.


OutcomesCumulative morphine request up to 48 h after surgery; pain scores at rest and movement-evoked; area of hyperalgesia; global quality of analgesia management; Long term: any pain in the scar area and any unpleasant experience since the operation


NotesCo-analgesia: epidural bupivacaine, sufentanil, clonidine


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"According to a computer-generated table of random number assignments"...

Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"All studied solutions were prepared by an anesthesiologist who was not involved in the patient's care. The patient and the anesthesiologist who delivered anesthesia and evaluated analgesia also were blinded to the study solutions".

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskThe incidence and importance of postoperative residual pain was evaluated at 2 weeks, 1 month, 6 months and 1 year after surgery. Patients were asked to answer the following questions…..This inquiry was performed by phone and confirmed by mail.

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced across groups and < 20%

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasHigh riskFewer than 50 patients per arm

Duale 2009

MethodsSingle center, randomized, double-blind, placebo-controlled trial with long-term follow-up for 6 weeks and 4 months


Participants86 patients between 20 and 75 years of age scheduled for elective partial pneumonectomy under thoracotomy were considered for inclusion


InterventionsRacemic ketamine was diluted to 500 mg in 500 mL of isotonic saline.1 mL per kg of the solution was given 5 min before surgical incision, and 1 mL per kg/h until skin closure. For the postoperative period, 1 mg per kg of ketamine was diluted in isotonic saline in a 48 mL-syringe, then infused at the rate of 2 mL per h (i.e. 1 mg per kg for 24 h), then discontinued. In the placebo group, isotonic saline was given alone following the same protocol.


OutcomesThe primary endpoint was to assess whether ketamine was able to reduce the pain score at the 6th week after surgery, compared to placebo. The secondary endpoints were to compare the early postoperative pain parameters, the rate of side effects, the late parameters of pain and the quality of life between the 2 groups.Morphine consumption (in mg), pain at rest (VAS from 0 to 10), sedation (scale from 0 to 3), nausea, vomiting, dizziness, pruritus, sensation of dry mouth, and current vital parameters.Area of sensory abnormalities (hypoesthesia, allodynia, hyperalgesia. The neuropathic pain symptom inventory and the SF-36 were also filled out.


NotesCo-analgesia: Before skin closure, the edges of the thoracotomy as well as the chest drainage orifices were infiltrated with 0.1% ropivacaine. In addition to the intraoperative ropivacaine infiltration, postoperative analgesia was ensured with interpleural 0.2% ropivacaine (40 mL into the chest tube clamped for 20 min), intravenous paracetamol (1 g every 6 h), nefopam (80 mg per 24 h in continuous infusion) and morphine. Ambulatory treatment of pain with acetaminophen/codeine.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskSequence generation is not stated

Allocation concealment (selection bias)Low risk"Randomisation was undertaken by a research assistant who was not involved in the observations. An inclusion number was allocated randomly and kept in a sealed envelope".

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"When the patient arrived at the operating theatre, the anaesthetist checked the randomisation, which was kept secret to the patient throughout the study".

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"All the observers of the study (i.e. nurses in recovery room and surgical ward, investigators and research assistants) were unaware of the treatment given, throughout the study".

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced across groups

Selective reporting (reporting bias)Low riskProtocol was registered and no differences were noticed compared with publication

Other biasHigh riskFewer than 50 patients per arm

Dullenkopf 2009

MethodsSingle center, randomized, double-blind, 3 arms, placebo-controlled trial with long-term follow-up for 3 months


Participants120 adult patients undergoing general or orthopedic operations anticipated to last 30 to 120 minutes


InterventionsThe study medication for all 3 groups was prepared and blinded by the hospital pharmacist. A syringe containing 12 ml was provided for every patient. One ml of the study solution contained 1.5 mg, 5 mg or 0 mg of ketamine in groups Kl, Km and P, respectively. In all patients, 1 ml of the study solution was administered for every 10 kg of body weight, resulting in 0.15 mg/kg ketamine IV, 0.5 mg/kg ketamine IV or normal saline in groups Kl, Km and P, respectively.


OutcomesAnesthetic consumption, time from skin closure to emergency, sedation score, ketamine side effects profile,  pain management categorical score. At 3 months: pain scores at rest and movement evoked, pain management score from excellent to poor


NotesCo-analgesia: novaminsulfone 1 gram + IV morphine and paracetamol


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"On the basis of a computer-generated block randomisation"

Allocation concealment (selection bias)Low risk"The study medication for all 3 groups was prepared and blinded by the hospital pharmacist".

Blinding of participants and personnel (performance bias)
All outcomes
Low riskSolutions were prepared in a blinded fashion by the pharmacist

Blinding of outcome assessment (detection bias)
All outcomes
Low riskPatients replied by mail 3 months later. Unclear if they were still blinded

Incomplete outcome data (attrition bias)
All outcomes
High riskThe proportion of missing outcomes (27.3%) compared with observed event risk enough to induce clinically relevant bias

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasHigh riskFewer than 50 patients per arm

Eisenberg 2007

MethodsSingle center, randomized, double-blind, placebo-controlled trial with long-term follow-up for 1 and 6 months


Participants22 Patients aged 18 to 75 years with breast cancer requiring mastectomy and axillary lymph node dissection. Subjects with any kind of chronic pain were excluded


InterventionsTreatment was initiated on the day before surgery and continued daily for 14 consecutive days. The dosing schedule was 100 mg of amantadine sulfate tablets twice daily. Patients in the placebo group received equal numbers of identical-looking placebo tablets according to the same schedule.


Outcomes0-10 pain scores, rescue medications, multidimensional pain evaluation. 3 months evaluation: 0-10 pain intensity across 5 different anatomical areas, coanalgesia and non pharma treatments, chemotherapy, hormone or Rxtherapy, Short Form-McGill Pain Questionnaire, sensory examination at medical visit (1 month and 6 months)


NotesPatients were allowed to use rescue medications, including opioids, simple analgesics (paracetamol or dipyrone), and non-steroidal anti-inflammatory drugs (NSAIDs)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Randomization was done in blocks of 4 according to a pre-prepared random code"...unclear how the sequence generation was created.

Allocation concealment (selection bias)Unclear riskNot stated in the publication

Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk"Both the amantadine and the placebo tablets were supplied by Merz  Co, Frankfurt, Germany"…unclear if the placebos matched the active drug.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskUnclear if outcomes assessors were blinded

Incomplete outcome data (attrition bias)
All outcomes
High riskMissing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups. However the proportion of missing data was > 20%

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasUnclear riskFewer than 50 patients per arm

Fassoulaki 2001

MethodsSingle center, randomized, double-blind, placebo-controlled, 4 arms trial for 3 months


Participants100 adult female patients, ASA I or II, scheduled for cancer breast surgery


Interventions4 arms combining ropivacaine (brachial plexus + Intercostal infiltration); mexiletine 200 mg BID for 6 days starting the night before surgery, and placebos


OutcomesPain scores at rest and movement-evoked in the acute setting; Three months after surgery, all patients responded to a structured phone interview to determine if they had: radiotherapy and/or chemotherapy; pain in the chest, axilla, arm of the operated side; reduced or absent sensation in the same areas; the average pain score (from 0 to 10) during the 3 months, if present; and the need for analgesics since they were discharged from the hospital.


NotesCo-analgesia: propoxyfene and paracetamol; 24 hours after surgery: codeine + paracetamol


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information to permit judgement

Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskInsufficient information to permit judgement

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskThree months after surgery, all patients responded to a structured phone interview to determine if they had…unclear if the interviewer was blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced across groups and < 20%

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasHigh riskFewer than 50 patients per arm

Fassoulaki 2002

MethodsSingle center, randomized, double-blind, placebo-controlled trial for 3 months


Participants75 ASA I or II female patients scheduled for breast surgery for cancer were recruited


InterventionsPatients were blindly randomized to one of 3 groups. In the mexiletine group, patients received 200 mg of mexiletine along with placebo capsules (identical in appearance to the gabapentin capsules) 3 times per day. Patients in the gabapentin group received 400 mg of gabapentin and placebo capsules (identical in appearance to the mexiletine capsules) 3 times per day. Patients in the placebo group received both placebo capsules 3 times per day. Administration of the active and/or placebo drugs started the evening before surgery and continued 3 times a day for the first 10 postoperative days, including the day of surgery.


OutcomesThe visual analog scale score assessed pain at rest and after movement. 3 months later, all patients were interviewed to identify intensity of chronic pain and analgesic requirements


NotesCo-analgesia: propoxyfene and paracetamol


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Each patient was randomly assigned to a treatment group, and the first dose was given the evening before surgery"

Allocation concealment (selection bias)Low risk"Seventy-five envelopes were prepared, coded as Group 1, Group 2, and Group 3, sealed, and opened for each patient to indicate the group of assignment".

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Envelopes, bottles with capsules, and coding were prepared by an anesthesiologist in cooperation with the hospital’s pharmacy. This anesthesiologist did not participate in the study, evaluation of the patients or data, or in report of the findings."

Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk"Three months after surgery, patients were interviewed by phone to identify whether they received postoperative chemotherapy, radiotherapy, or both and if they experienced pain or abnormal sensations in the chest, axilla, or the arm of the operated side"

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced across groups and < 20%

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasHigh riskFewer than 50 patients per arm

Fransen 2006

MethodsMulticenter, randomized, double-blind, placebo-controlled trial for a variable follow up time (6-14 months)


Participants902 Patients identified within 24 hours of completed THR (primary or revision), irrespective of age, reason for surgery, or procedure performed


InterventionsIbuprofen 1200 mg Daily (TID) for 14 days


OutcomesPrimary outcomes: changes from baseline to follow-up in WOMAC. We standardised scores to a range of 0-10, with 0 indicating no hip pain or no difficulty with daily activities and 10 indicating severe hip pain or severe difficulty with daily activities. Secondary outcomes: Short form 36, compared with before surgery; hip status today with 5 response levels; frequency of use of analgesia for hip pain during the past week; ability to get “about the house” and ability to get “out of the house” with 5 response levels ranging from “not at all” to “no difficulty”; time spent participating in physical activity during the past week; objective measures of physical performance (hip flexion, time to walk 50 feet (about 15 metres), and timed “up and go”; radiographic evidence of ectopic bone formation according to the Brooker classification and major bleeding complications during hospital admission.


NotesCo-analgesia was up to treatment group. No changes in the NSAIDs were allowed


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomisation was performed centrally by using a computer based system"

Allocation concealment (selection bias)Low risk"We used a minimisation program to stratify treatment by study centre and type of surgery performed (primary or revision). Treatment allocation was blinded and concealed from patients and study staff until the database was locked".

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"All study tablets were packaged in identical blister packs".

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"All assessments were standardised and performed blind to randomised treatment allocation".

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo statistical significant difference in the rate of dropouts. (P=0.06). The proportion of missing outcome data < 20%

Selective reporting (reporting bias)Low riskProtocol was registered and no differences were noticed compared with the publication

Other biasLow riskNo other potential sources of bias were detected

Gianesello 2012

MethodsSingle center, randomized, double-blind, placebo-controlled trial with follow-up for 2 days, 3 months and 1 year after surgery


Participants60 adult patients of either sex, having American Society of Anesthesiologists physical status I-II, scheduled for elective decompressive lumbar laminectomy with spinal fusion for degenerative spinal stenosis.


InterventionsPatients were randomly assigned to 2 equal groups of 30 each using a computer-generated table of random numbers to receive either a matching PL or PG 300 mg (Lyrica; Pfizer) and PL or PG 150 mg, twice a day for 48 hours postoperatively.


OutcomesPain scores at rest and movement-evoked, Ramsay sedation scale, incidence of respiratory depression, hypotension and other side effects. Patients were called at 3 months to evaluate EuroQoL and perceived general health status.


NotesCo-analgesia: intraoperative dexamethasone + POP morphine infusion and ketorolac


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Patients were randomly assigned to 2 equal groups of 30 each using a computer-generated table of random numbers".

Allocation concealment (selection bias)Low risk"All of the medications were identical, were provided by the hospital pharmacy".

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"All of the medications were identical"

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Patients were questioned during the first 1 hour in the postanesthesia care unit and were later evaluated in the ward at 4, 8, 12, 24, and 48 hours by an independent observer blinded to group allocation".

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasHigh riskFewer than 50 patients per arm

Grigoras 2012

MethodsSingle center, randomized, double-blind, placebo-controlled trial with a daily follow-up for 7 days, and sensory examination 3 months after surgery


Participants36 American Society of Anesthesiology physical status I or II patients undergoing breast surgery (mastectomy or wide local excision+axillary node dissection, including sentinel node mapping or clearance) were undertaken


InterventionsImmediately after orotracheal intubation, patients of the lidocaine group (L) received an IV bolus of lidocaine (1.5 mg/kg in 10 min) followed by a continuous IV infusion at 1.5 mg/kgh. The infusion was stopped 60 minutes after skin closure. Patients in the control group (C) received an equivalent saline regimen.


OutcomesVisual analog scale (VAS) pain scores at rest and on arm movement was recorded at 2, 4, 24, 48, and 72 hours postoperatively, or at these time points until discharge from hospital; analgesic use was recorded for each group; A questionnaire was also used to assess the presence or absence of persistent pain, the time of onset, location and character of the pain, medications used for pain relief and impact on the patients’ daily life, a history of chemotherapy or radiotherapy, and further surgery. PPSP was considered to be present if the answer to “Have you had pain in the last week which you attribute to your breast surgery?” was “Yes.”; Three months postoperatively, patients had the area of peri-incisional hyperalgesia measured by the same blinded investigator and completed the short-form McGill Pain Questionnaire, the Pain Catastrophizing Scale, and the Hospital Anxiety and Depression Scale.


NotesIntraoperative analgesia in both groups consisted of paracetamol IV 1 g, diclofenac IV 75 mg, and morphine sulphate PRN IV. Morphine was administered after induction of general anesthesia and titrated according to patient response to surgical stimuli.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Patients were randomly allocated to 1 of 2 groups based on computer generated codes that were maintained in
sequentially numbered opaque envelopes".

Allocation concealment (selection bias)Low risk"None of the investigators involved in patient management or data collection were aware of the group assignment".

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"On the morning of surgery an anesthetist who was not involved in the patient’s evaluation opened the envelope and prepared either 1% lidocaine or normal saline in coded 50mL syringes".

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Three months postoperatively, patients had the area of peri-incisional hyperalgesia measured by the same blinded investigator"....

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe study reported no missing outcome data at 3 months

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasHigh riskFewer than 50 patients per group

Hayes 2004

MethodsSingle center, randomized, double-blind, placebo-controlled trial with follow-up for days 3, 6 + 6 months after surgery


Participants45 Patients presenting for above- or below-knee amputation because of peripheral vascular disease, cancer or chronic infection


InterventionsThe Ketamine patients received a pre-induction intravenous (IV) bolus of ketamine 0.5 mg.kg–1, + IV infusion at 0.15 mg.kg/h. Control patients received a pre-induction IV bolus of normal saline, followed by IV infusion. Trial solutions were continued for 3 days postoperatively. If side-effects considered attributable to ketamine occurred (vivid dreams, hallucinations or confusion), the infusion rate was halved. If side-effects then continued or were severe, the infusion was ceased.


OutcomesOpioid consumption at 24 and 72 hours, complications, patient satisfaction, phantom or stump pain incidence. 0-10 Pain scores (highest, lowest, usual and current level). Sensory examination with von Frey filaments including measurement of the area of sensitization.


NotesCo-analgesia: morphine PCA. Amitriptyline and sodium valproate were used to treat phantom limb pain


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Patients were randomized (via a random number generator) to receive"...

Allocation concealment (selection bias)Unclear riskNot stated

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"The patient, anaesthetist, Acute Pain Service (APS) personnel, ward staff and investigators were blinded to the contents of the trial solution".

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"The patient, anaesthetist, Acute Pain Service (APS) personnel, ward staff and investigators were blinded to the contents of the trial solution".

Incomplete outcome data (attrition bias)
All outcomes
High riskSignificant proportion of missing outcome data (>20%)

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasHigh riskFewer than 50 patients per group

Ilkjaer 2000

MethodsSingle center, randomized, double-blind, placebo-controlled trial with follow-up for days 3  months after surgery


Participants50 patients scheduled for non-malignant elective abdominal hysterectomy with a supravaginal, horizontal approach


InterventionsOne hour before surgery, patients received dextromethorphan 150 mg or placebo (5 tablets) orally as premedication


OutcomesPressure pain detection threshold, von Frey pain detection threshold and hyperalgesia to von Frey hair stimulation proximal to the surgical wound, were assessed 3 months after the operation, during a control visit at the hospital.


NotesCo-analgesia: intraoperative fentanyl. Postoperative: PCA morphine


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information to permit judgement

Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"The study drugs (identical tablets of dextromethorphan 30 mg, or vehicle without dextromethorphan)".

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes
Low riskExcluded patients were replaced until 50 data sets were available for analysis

Selective reporting (reporting bias)High riskthe authors reported sensory examination, however, it would be more clinical meaningful the report of pain scores or at least the rate of residual pain

Other biasHigh riskFewer than 50 patients per group

Karanikolas 2011

MethodsSingle center, randomized, double-blind, placebo-controlled trial with follow-up for days 6  months after surgery


Participants65 patients > 18 yr with severe pain (VAS > 60 /100) one week before scheduled lower-limb amputation


InterventionsThe study had five groups that received intravenous PCA Fentanil or Epidural fentanyl, which was started 2 days before surgery until the second postoperative day. One of the groups represented the "conventional analgesia" that included IM Meperidine and codeina/acetaminophen.


OutcomesThe results of the visual analog scale and the McGill Pain Questionnaire were recorded perioperatively and at 1 and 6 months


NotesPatients received IV intraoperative remifentanil, too


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomization was performed using computer-generated blocks".

Allocation concealment (selection bias)Low risk"Each patient assigned to participate in the study had a sequentially numbered sealed envelope containing a randomization code. The envelopes were concealed until after consent was obtained".

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"….control group patients had an epidural catheter placed subcutaneously at the L4 interspace in the lumbar area and received N/S at 2 ml/h. In addition, they had a second infusion pump that administered patient-controlled intravenous N/S".

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"...A second blinded investigator (G.M.) interviewed all patients before the beginning and after the end of the analgesic protocol (at 4- and 10-day and at 1- and 6-month follow-up), whereas a third blinded investigator (M.K.) conducted all interviews during the analgesic protocol (at least at 8-h intervals)".

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data were minimum and balanced across groups

Selective reporting (reporting bias)Low riskProtocol was registered and no significant differences were noticed compared with publication…except for the pain intensity inclusion criteria (> 70/100 in the protocol)

Other biasHigh riskFewer than 50 patients per arm

Katz 2004a

MethodsSingle center, randomized, double-blind, placebo-controlled trial with follow-up for days 3, 14 and 6 months after surgery


Participants141 patients scheduled for radical prostatectomy for prostate cancer. Inclusion criteria were ASA I-II, age between 19 and 75 years


InterventionsTwo 60 ml coded syringes were used labelled as pre-incision and post-incision. Every syringe had ketamine (1mg/ml) or saline. Group 1: PRE Ketamine POST: Saline; Group 2: PRE Saline POST Ketamine; Group 3: Both had saline. 10 minutes before incision. All patients received i.v. fentanyl (1 mcg/kg) every 80 min starting approximately 5 min before induction of general anesthesia. Approximately 10 min before skin incision, and after induction of general anesthesia, all patients received a bolus dose of i.v. fentanyl (0.5 mcg/kg). This was followed immediately by an i.v. bolus dose (0.2 ml/kg) and an i.v. infusion (0.0025 ml/kg/min) from the first syringe labelled ‘pre-incision’. Seventy minutes after incision, the first infusion was stopped and all patients received a bolus dose of i.v. fentanyl (0.5 mcg/kg). This was followed immediately by an i.v. bolus dose (0.2 ml/kg) and an i.v. infusion (0.0025 ml/kg//min) from the second syringe labelled ‘post-incision’. The second infusion was stopped after 80 min, approximately 150 min after incision.


OutcomesVisual analogue pain scores at rest and movement (first 3 days); pain rating index, and present pain intensity. Touch and Pain Threshold using the von Frey filament (at 2 weeks follow up), Mental Health Inventory, Spielberg state-Trait Anxiety Inventory, At 6 months, patients were followed with the Follow-Up Questionnaire (FUPQ).


NotesCo-analgesia: intraoperative IV fentanyl; PCA morphine after surgery


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"A randomization schedule was computer-generated"…

Allocation concealment (selection bias)Low risk"An opaque envelope containing the patient number and group assignment was prepared, sealed and numbered for each patient by the hospital pharmacist".

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"All patients and personnel involved in patient management and data collection were unaware of the group to which the patient had been allocated. The anesthesiologist in charge of the case was also unaware of group allocation".

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"All patients and personnel involved in patient management and data collection were unaware of the group to which the patient had been allocated. The anesthesiologist in charge of the case was also unaware of group allocation".

Incomplete outcome data (attrition bias)
All outcomes
Low riskA proper method for incomplete outcome data was performed for analysis

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasLow riskNo other potential sources of bias were detected

Kim 2010

MethodsSingle center, randomized, double-blind, placebo-controlled trial for 3 months


Participants99 ASA class I–II patients, aged 20–65 years, with thyroid cancer were scheduled for elective robot-assisted endoscopic thyroidectomies and included in this study.


InterventionsAccording to their assigned study group, patients received pregabalin 150 mg or placebo twice—1 h before surgery and 12 h after the initial dose. All pills were administered by a nurse who was not involved in the study.


OutcomesPain scores, side effects profile, and incidence of anterior chest hypoesthesia


NotesCo-analgesia: intraoperative ketorolac and POP ibuprofen


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Patients were randomly assigned to one of 2 groups to receive….

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"The drugs were provided by the hospital pharmacy as identical capsules to ensure blinding."

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Patients, the surgeon, and the anesthesiologist responsible for follow-up during the postoperative period were blinded to group allocation."

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced across groups and < 20%

Selective reporting (reporting bias)Low riskProtocol was registered and no significant differences were noticed compared with publication

Other biasLow riskNo other potential sources of bias were detected

Kinney 2011

MethodsSingle center, randomized, double-blind, placebo-controlled trial for 3 months


Participants120 patients aged 45 - 75 years undergoing elective thoracotomy


InterventionsPatients were allocated to receive either 600 mg of gabapentin or active placebo (diphenhydramine 12.5 mg) orally within 2 hours preoperatively


OutcomesPain scores in the acute setting + side effects of the medications. Telephone call: surgical site pain


NotesCo-analgesia: thoracic epidural analgesia, POP fentanyl, ketorolac and acetaminophen


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Using a block randomization schedule stratified by surgeon…

Allocation concealment (selection bias)Low risk"All members of the surgical, nursing, and acute pain service teams were blinded to group assignment".

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Placebo capsules of identical shape and size to commercially available gabapentin were manufactured by the hospital pharmacy"

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"All outcome assessors were blinded to group allocation".

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced across groups and < 20%

Selective reporting (reporting bias)Low riskProtocol was registered and no significant differences were noticed compared with publication

Other biasLow riskNo other potential sources of bias were detected

Lakdja 1997

MethodsSingle center, randomized, double-blind, placebo-controlled trial for 6 months


Participants30 patients with adenocarcima requiring total or partial mastectomy with axillary dissection


InterventionsIbuprofen: 400 mg 90 minutes before surgery, 2 h after and then q8h up to 32 hours after surgery


OutcomesPain Scores: VAS in the first 42 hours after surgery. At 6 months, consultation. They evaluated the need of adjuvant radiotherapy, the presence of dysesthesia, allodynia, paresthesia or hyperthesia that lasted more than 3 months and was present during the exam: SDPM: postmastectomy pain syndrome. 


NotesCo-analgesia: 300 mcg of intraoperative fentanyl, POP analgesia: PCA morphine


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information to permit judgement

Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskInsufficient information to permit judgement

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced across groups and < 20%

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasHigh riskFewer than 50 patients per group

Malek 2006

MethodsSingle center, randomized, double-blind (patients and outcomes assessor nurse), placebo-controlled trial for 6 months


Participants100 women scheduled for breast cancer surgery


InterventionsKetamine 1 mg/k/day in IV infusion for 2 days


OutcomesAfter 6 months of surgery patients received a questionnaire concerning the presence of chronic pain, its intensity (1 - mild, 2-medium, 3 - strong, 4 - Unbearable), quality (constant vs intermittent), location (in scars, in the whole breast or chest wall, armpit, elsewhere) and nature (using the modified McGill Pain Questionnaire).


NotesCo-analgesics: preoperative and postoperative meperidine + intraoperative sufentanil


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskDrawing lots

Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskPatients were blinded. However, the person that prepared the solutions is unclear if he/she was blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskPatient filled out a questionnaire at 6 months. However is unclear if already knew what received during surgery

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information to permit judgement

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasLow riskNo other potential sources of bias were detected

Moore 2011

MethodsSingle center, randomized, double-blind, placebo-controlled trial for 3 months


Participants46 pregnant women 18 years or older, undergoing scheduled cesarean delivery


Interventions600 mg of oral gabapentin 1 hour before the surgery


OutcomesPain scores, satisfaction with pain management, sedation, supplemental analgesia. At 3 months: sensory abnormalities and pain scores


NotesCo-analgesia: IT morphine, intraoperative fentanyl, POP IV morphine, oral diclofenac, oral acetaminophen


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"According to a computer-generated randomization…

Allocation concealment (selection bias)Low risk"According to a computer-generated randomization table known only to the pharmacy department, the gabapentin or placebo capsules were then placed in sequentially numbered envelopes".

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"...identical blue capsule covers".

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported

Incomplete outcome data (attrition bias)
All outcomes
High riskMissing outcome data balanced across groups; however, the missing outcome data is > 20%

Selective reporting (reporting bias)Low riskProtocol was registered and no significant differences were noticed compared with publication

Other biasHigh risk"The study was terminated after 46 patients because a very low recruitment rate led to prolongation of the study".

Nikolajsen 2006

MethodsSingle center, randomized, double-blind, placebo-controlled trial for 3 and 6 months


Participants46 adults undergoing lower limb amputation because of peripheral vascular disease


InterventionsPatients received one capsule (300 mg gabapentin or placebo) on the first postoperative day, 3 capsules (900 mg) on days 2–4, 4 capsules (1,200 mg) on days 5 and 6, 5 capsules (1,500 mg) on days 7 and 8, 6 capsules (1,800 mg) on days 9 and 10, seven (2,100 mg) capsules on days 11 and 12, and eight capsules (2,400 mg) on days 13–30. Patients with a creatinine clearance 30 ml/min but 60 ml/min received a maximum dose of 1,200 mg. If patients experienced intolerable side effects before the maximum dose of 1,200/2,400 mg was reached, they were allowed to stay on a lower dose for the rest of the study period. Patients who did not tolerate a minimum dose of 900 mg were withdrawn from the study.


OutcomesPhantom limb and stump pain scores, McGill pain questionnaire, guessing about treatment


NotesEpidural Infusion of bupivacaine and opioid + paracetamol


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"….using a computer-generated randomization list in block sizes of 8 and 10".

Allocation concealment (selection bias)Low risk"During the study, the randomization list was held securely at the hospital pharmacy and released only after study completion".

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"After 30 days of treatment, 10/39 patients correctly identified the treatment given".

Blinding of outcome assessment (detection bias)
All outcomes
Low riskIn 5 cases, the investigator correctly identified the treatment given: gabapentin: side effects (n =  3); placebo: lack of effect (n  = 2). In 8 cases, the answers were incorrect, and in 26 cases the treatment could not be identified

Incomplete outcome data (attrition bias)
All outcomes
High riskSignificant number of drop outs (26.1%) and incomplete treatments

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasHigh riskSmall sample size, pain intensity was low in both treatment groups; fewer than 50 pts per arm

Perrin 2009

MethodsSingle center, randomized, double-blind, placebo-controlled trial with follow-up for days 1, 2; long term FU: 6 months after surgery


Participants12 patients booked for elective unilateral total knee arthroplasty with an ASA I to III


InterventionsA programmed syringe delivered ketamine 0.5 mg/kg bolus followed by 4 μg/kg/min infusion, or equivalent volumes of the saline solution. The infusion commenced before surgical incision and continued until the surgical wound was bandaged or the syringe was empty.


OutcomesNumerical rating scale pain scores at rest and movement (pressure care turning) were collected at 4, eight, 12, 16 and 20 hours post intrathecal injection and averaged to give a first 24-hour pain ‘score’ with a denominator of 10. The next 5 pain enquiries from 24 to 40 hours were poorly recorded and are not presented. 48 h morphine request; Primary outcome measures 1. Incidence of pain at 6 months equal to or worse than that preoperatively using WPS; 2. Incidence of zero pain in operated knee at 6 months using WPS; 3. Presence of pain not meeting the above criteria, arbitrarily labelled mild/moderate.


NotesParacetamol 750 mg 24h, PCA morphine, ibuprofen 800 mg PRN


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information to permit judgement

Allocation concealment (selection bias)Low riskThe sealed syringe code was stored in our pharmacy department

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe publication states that the study is triple blind

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes
High riskSignificant number of drop outs (25%) and incomplete treatments

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasHigh riskFewer than 50 patients per arm

Pesonen 2011

MethodsSingle center, randomized, double-blind, placebo-controlled trial for one and 3 months


ParticipantsSeventy patients, aged 75 yr or older and undergoing primary elective coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB) or single valve repair or replacement with CPB, were initially included in the study.


InterventionsBeginning on the first postoperative morning, patients received 75 mg pregabalin or placebo twice daily until the fifth postoperative day.


OutcomesPain scores, Richmond Agitation, Sedation Score, oxycodone consumption, ICU stay, paracetamol requirement


NotesCo-analgesia: paracetamol, oxycodone


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"pharmacy performed the randomization using a computer generated randomization schedule"

Allocation concealment (selection bias)Low risk"Each consenting patient received the study drug according to a consecutive randomization number, which was labelled to opaque plastic containers containing the study drugs".

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"The pharmacy also prepared the study medication by packing pregabalin or placebo into identical capsules for blinding".

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"The Verbal Rating pain score at rest and during movement and the analgesics consumed were recorded in a telephone interview by a blinded interviewer 1 and 3 months after the surgery".

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced across groups and < 20%

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasHigh riskFewer than 50 patients per arm

Remerand 2009

MethodsSingle center, randomized, double-blind, placebo-controlled trial with follow-up for days 1, 14, 30, 90 and 6 months after surgery


Participants154 adult patients scheduled for a total hip arthroplasty


InterventionsPatients received an IV bolus of 0.5 mg/kg ketamine (maximum 50 mg) from the first blinded 5-mL syringe, followed by a 24-h infusion using the second study syringe at 2 mL/h (equivalent to 2 mcg/Kg/min).


Outcomes"Morphine consumption during the first 24 postoperative hours was our primary outcome".


NotesCo-analgesia: intraoperative sufentanil, POP paracetamol, ketoprofen, PCA morphine (day 1), oral morphine (day 2-4)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk" as part of a computer generated randomization process"....

Allocation concealment (selection bias)Low risk"160 identical white envelopes were prepared, numbered, and sealed by a person external to our clinical unit. Each envelope contained detailed instructions of the preparation of 2 syringes (ketamine or saline). On the morning of the THA, a nurse prepared 2 syringes as described in the instructions, left them in a sterile box, and had no further clinical or research involvement".

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Nurses, anesthesiologists, and surgeons were unaware of the group assignment until the end of the study".

Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk"Patients were interviewed by phone on Days 30, 90, and 180 for pain location and intensity (at rest and while walking), need for help when walking, and analgesic consumption, by 1 of the 2 first authors". Insufficient information to permit judgement.

Incomplete outcome data (attrition bias)
All outcomes
Low risk"The study size was then set at 80 patients per group, to compensate for possible dropout patients and the fact that randomization was not created in blocks. In case of incomplete follow-up, missing data were excluded from analysis, but the remaining data (before any missing phone interview) were analyzed".

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasLow riskNo other potential sources of bias were detected

Romundstad 2006

MethodsSingle center, randomized, double-blind, 3 arms, placebo-controlled trial with follow-up for days 6 weeks and 1 year after surgery


Participants219 patients (20-45 yo) underwent breast augmentation surgery


InterventionsSingle i.v. preoperative dose of methylprednisolone 125 mg, parecoxib 40 mg or saline


OutcomesThe primary outcome variable was prevalence of pain at rest. Secondary outcome variables were prevalence of evoked pain, and sensory changes.


NotesIntraoperative: fentanyl + infiltrative (intercostal) Lidocaine+adrenaline. POP: acetaminophen 500 mg/codeine 30 mg


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"A person not involved in the treatment and follow-up of patients randomized the patients in blocks of nine to 1 of 3 groups of equal size using a list of random numbers, according to the Moses-Oakford algorithm".

Allocation concealment (selection bias)Low risk"Block size and randomization code were not revealed to the investigators until all measurements and calculations had been entered into the database".

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Methylprednisolone (Solu-Medrol) 125 mg, parecoxib 40 mg, and placebo (NaCl) were prepared at Rikshospitalet University Hospital by a doctor not in contact with the observers or patients. Test drugs were diluted with saline to fill a 10-mL syringe, marked with patient number and the possible test drugs, and appeared identical for all persons involved in the trial".

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Neither the person conducting the interview nor the patients were aware of the group to which the patients were assigned".

Incomplete outcome data (attrition bias)
All outcomes
Low risk Missing outcome data balanced in numbers across intervention groups

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasLow riskNo other potential sources of bias were detected

Schley 2007

MethodsSingle center, randomized, double-blind, placebo-controlled trial with a long term FU up to 6 months


Participants19 patients scheduled for amputation of at least one finger


InterventionsMemantine: First week: 10 mg/day; second week: 20 mg/day; Week 3 and 4th: 30 mg/day versus placebo matched pills


OutcomesPrimary outcome variable was intensity of Phantom Limb Pain (PLP). Secondary outcome parameters were prevalence PLP, intensity of stump pain, phantom sensation and stump sensation. Intensity of these sensations was recorded via visual analogue scale (VAS 1–100) upon (1) admission; (2) before primary block; (3) 30 min after primary block; (4) twice daily during hospitalization; (5) 4 weeks after end of memantine treatment; (6) 6 and 12 months after end of memantine treatment.


NotesCo-analgesia: brachial plexus block for one week after the amputation. Intraoperative sufentanil


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information to permit judgement

Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Patients and treating physicians were blinded for the medication".

Blinding of outcome assessment (detection bias)
All outcomes
Low risk…..Also data acquisition and processing were performed in a blinded fashion

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk9/30 patients patients redraw their agreement briefly after beginning of the treatment. Reasons are not stated

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasUnclear riskBefore the beginning of treatment (admission) 11 of 19 patients (58%) had developed PLP: 6 patients (60%) in memantine group and 6 patients in the control group.

Sen 2009

MethodsSingle center, randomized, double-blind, placebo-controlled trial for 3 and 6 months


ParticipantsSixty male patients – aged 20–40 years, ASA I – who were scheduled for unilateral elective indirect inguinal herniorrhaphy under spinal anaesthesia


InterventionsIn the gabapentin group, a single dose of 1.2 g oral gabapentin was given to patients 1 h before surgery; in the placebo group, a placebo capsule was given 1 h before surgery.


OutcomesPain scores, side effects, sedation, nausea, vomiting


NotesCo-analgesia: tramadol in PCA for 24 h. Rescue analgesia with diclofenac


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"randomly allocated into 2 groups (according to computer-generated randomization)".

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"All measurements were recorded by the same anaesthesiologist who was blinded to the study groups".

Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk"Assessment of postoperative pain at 1, 3 and 6 months was carried out – via telephone – with an 11-point numerical rating scale (NRS); 0 indicating ‘no pain’ and 10 indicating ‘worst pain imaginable’".

Incomplete outcome data (attrition bias)
All outcomes
Low riskMinimum missing outcome data

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasHigh riskFewer than 50 patients per arm

Sen 2009a

MethodsSingle center, randomized, double-blind, placebo-controlled trial for 3 and 6 months


ParticipantsSixty women scheduled for abdominal hysterectomy


InterventionsThe patients were assigned to 1 of the 3 treatment groups. The control group received oral placebo capsules and bolus plus infusion of saline; the ketamine group received oral placebo capsules and, before incision, 0.3 mg/kg IV bolus and 0.05 mgkg1h1 infusion of ketamine until the end of surgery11; and the gabapentin group received oral gabapentin 1.2 g and bolus plus infusion of saline.The initial dose of the study medication was administered 1 h before surgery.


OutcomesPain scores, sedation scale, morphine requirement, recovery of bowel function, patient satisfaction


NotesCo-analgesia: intraop morphine + morphine PCA + codeine acetaminophen


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"The patients were randomly assigned to 1 of the 3 treatment groups using a computer-generated table".

Allocation concealment (selection bias)Low risk"All study drugs were prepared by the hospital pharmacy, and an appropriate code number was assigned to each patient".

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"The same label was used for all the infusions for blinding purposes".

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"All measurements were recorded by a research assistant who was blinded to the study medication. Patients were also contacted by one of the investigators at 1, 3, and 6 mo after discharge to inquire as to when they were able to resume normal activities of daily living (i.e., return to work) and if they had any residual postoperative (incisional) pain".

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasHigh riskFewer than 50 patients per arm

Spreng 2010

MethodsSingle center, randomized, double-blind, placebo-controlled trial with scheduled follow ups at 7 and 90 days after surgery


Participants77 patients > 18, ASA I-II scheduled for day-care elective hemorrhoidectomy


InterventionsApproximately 1 h before surgery all patients received oral paracetamol 1-2 grams. Total Intravenous Anesthesia (remifentanil +propofol) was the anesthesia technique. During operation all patients received intravenous 8mg dexametahasone and 30mg ketorolac. After surgery, the surgeon injected 10–20 ml bupivacaine 2.5mg/ml + epinephrine in the surgical field. After insertion of laryngeal mask, but before start of surgery, patients in the (S)-ketamine group received an intravenous bolus dose of 0.35mgkg (S)-ketamine (Pfizer, 2.5mgml−1) followed by continuous infusion of 5gkg−1 min−1 (S)-ketamine. Patients in the placebo group received an equivalent volume of isotonic saline (bolus and infusion). Rescue pain medication was fentanyl 0.05–0.1mg IV during 0–30 min after end of surgery and paracetamol + codeine (500mg+ 30mg) orally later on; and was given when VAS > 30, NRS > 3 or upon patient request.


OutcomesVAS (0-100) pain scores and numerical rating scales (0-10). At 30 min after the end of surgery the patients completed the trail making test for evaluation of (S)-ketamine psychotomimetic side-effects: patient is asked to connect randomly distributed numbers (from 1 to 25) as fast as possible. At discharge from the PACU patients’ grade of satisfaction was registered (satisfied–indifferent–not satisfied) and need of rescue analgesics in the PACU was documented. The patients were interviewed by phone on postoperative day 1, day 7 and 3 months after surgery; assessing pain intensity, need for analgesics, grade of satisfaction and side-effects (nausea, hallucinations, double and/or abnormal colour vision).


NotesDexamethasone was administered at analgesic range + local analgesia infiltration, which increases the external validity of the results.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskThe method of sequence generation is not stated

Allocation concealment (selection bias)Low risk"Permuted block randomization, blinding and packing of the study medication were performed by the hospital pharmacy. The randomization codes were provided in sealed envelopes".

Blinding of participants and personnel (performance bias)
All outcomes
Low riskPatients in the placebo group received an equivalent volume of isotonic saline (bolus and infusion)

Blinding of outcome assessment (detection bias)
All outcomes
Low risk...."They were observed and evaluated by nursing staff which were blinded to the treatment. Pain intensity was assessed after 15, 30, 60 min and before discharge from PACU using visual analog scale (VAS, 0–100) and numeric rating scale (NRS, 0–10) for pain".

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskCompensating for missing data a total of 80 patients was planned for this study. However, It is unclear what proportion of patients was effectively contacted at the 3 months follow-up

Selective reporting (reporting bias)Low riskThe protocol was registered and the primary outcome fits with the primary outcome of the publication

Other biasHigh riskFewer than 50 patients per arm

Suzuki 2006

MethodsSingle center, randomized, double-blind, placebo-controlled trial with follow-up for days 1, 2, 30, 90 and 180 days after surgery


Participants50 patients who were scheduled to undergo open thoracotomy


InterventionsBefore Anesthesia induction, an epidural inserted and confirmed with ropivacaine. After tracheal intubation, an intravenous infusion of 0.05 mg/kg/h ketamine or placebo at the same volume was started. The infusion rate of ketamine was determined by simulation in a target-controlled infusion program to maintain a blood concentration of 20 ng/ml. After surgery, all patients received a continuous epidural infusion of 0.05 mg/ml morphine and 0.15% ropivacaine at an initial rate of 3 ml/h or by an infusion pump. Epidural infusion was continued for 48 h. All patients continued to receive infusion of ketamine or placebo for 72 h after surgery. If the patient requested additional analgesia within 24 h of surgery, 50 mg intravenous flurbiprofen was administered.


OutcomesThe primary endpoint of the study was the number of patients who felt baseline pain at 3 months after thoracotomy. In a long term, the outcomes were the number of patients who felt usual pain at 1, 3, and 6 months after surgery; the number of patients who were taking pain medication 1, 3, and 6 months after surgery; the number of patients who felt an unpleasant sensation on the surgical wound; and the number of patients who felt inconvenienced by the wound.


NotesCo-analgesia: epidural analgesia (ropivacaine + morphine for 48 hours)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Patients were assigned to one of 2 groups using a computer-generated randomization schedule".

Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe study drug, ketamine or placebo, was prepared and placed in the infusion pump by an investigator who did not participate in the administration of anesthesia or the evaluation of postoperative pain.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskAt 1, 3, and 6 months after surgery, one of the investigators, who did not know the group assignment, called each patient’s home and administered the same questionnaire that had been given on day 7.

Incomplete outcome data (attrition bias)
All outcomes
Low riskMinimum missing outcome data (12% only)

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasHigh riskFewer than 50 patients per arm

Sveticic 2008

MethodsSingle center, randomized, double-blind, placebo-controlled trial with follow-up for days 1, 2, 90 and 180  after surgery


Participants352 patients undergoing major elective orthopedic surgery


InterventionsMorphine PCA + ketamine (1mg:1mg). Boluses of 1.5 mg of each drug, max. 6 per 4


OutcomesPrimary outcome: rate of unsatisfactory treatment; secondary outcomes: mean pain scores at rest and movement-evoked; analgesic consumption; side effects profile; and incidence of pain at 3 months and 6 months


NotesCo-analgesia: intraoperative fentanyl; mepivacaine (50 ml) for nerve blockade or bupivacaine for spinal anesthesia; POP IV propacetamol + morphine PCA and ketorolac


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomization was performed by drawing lots immediately before administering the solution".

Allocation concealment (selection bias)Unclear risk"Patients were randomly allocated to receive PCA consisting of either morphine 1.5 mg (Group M) or morphine with ketamine 1.5 mg of each"…..Insufficient information to permit judgment

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"The patients, nurses who cared for patients, anesthesiologists who performed the anesthesia were not aware of the PCA drug used".

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"The investigators who gathered the data were not aware of the PCA drug used".

Incomplete outcome data (attrition bias)
All outcomes
High riskOnly 25.9% and 10.2% of all patients returned our chronic pain questionnaire 3 and 6 mo after the surgery, respectively

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasLow riskNo other potential sources of bias were detected

Ucak 2011

MethodsSingle center, randomized, double-blind, placebo-controlled trial for one, 3 and 6 months


Participants40 patients (34 men and 6 women) who were less than 80 years of age and undergoing elective CABG surgery with cardiopulmonary bypass (CPB) were enrolled.


InterventionsThe gabapentin group received orally 1.2 g/d 1 h before and 2 days after surgery, and the placebo group received a placebo capsule instead.


OutcomesPain scores, tramadol request, side effects, and pop morbidities


NotesIV tramadol and acetaminophen


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"The patients were assigned randomly into 2 groups (using a computer- generated table)".

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"A single nurse who was blinded to the study protocol prepared the placebo capsules and administered them to the patients. The doctors and nurses in the operating room, intensive care unit, and ward were blinded to the study protocol".

Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk"All patients completed a 1- and 3-month follow-up. The assessment of postoperative pain at 1 month was performed at the outpatient visits, and at 3 months it was carried out via telephone with a 10 point numeric rating scale".

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasHigh riskFewer than 50 patients per arm

Weis 2006

MethodsSingle center, randomized, double-blind, placebo-controlled trial with follow-up to 6 months after surgery


Participants36 high-risk patients undergoing cardiac surgery


InterventionsHydrocortisone: loading dose (IV 100 mg) before induction, followed by a infusion of 10 mg/h for 24 hours, which was reduced to 5 mg/h POD 2 and then tapered to 3X20 mg IV on POD 3 and 3  X 10 mg IV on day 4


OutcomesAcute period: Inotropic agents use and acute phase reactants. At 6 months the patients were contacted by telephone and received a detailed re-explanation of the purpose of the study. The authors measured SF-36, traumatic memories and chronic stress symptoms. 


NotesCo-analgesia is not stated


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe patients were randomly assigned to one of 2 treatment groups with the use of a computer-generated randomization list

Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgment

Blinding of participants and personnel (performance bias)
All outcomes
Low risk….received normal saline in identical vials in a double-blind fashion. The vials were prepared by a study nurse who was not involved in the care of patients participating in the trial.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskPatients returned questionnaires to the authors….

Incomplete outcome data (attrition bias)
All outcomes
High riskMissing data > 20%

Selective reporting (reporting bias)Low riskOutcomes reported are clinically meaningful and validated

Other biasHigh riskThe paper is unclear about the number of patients with any pain at 6 months. Fewer than 50 patients per arm

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Arcioni 2007The study evaluated regional/local techniques for analgesia

Bell 2001The study evaluated regional/local techniques for analgesia

Biyik 2009Open label study

Bone 2002Not preventive study; pain is already established

Buvanendran 2003Patients were followed for less than 3 months

Camilleri 2001The study used a population out of the scope of the review (non surgical/late postsurgical setting)

Capdevila 1999The study reported outcomes in the acute setting only

Chiu 2008The study evaluated regional/local techniques for analgesia

Clarke 2010The study is a secondary analysis of Clarke 2009

Cobellis 2004The study used a population out of the scope of the review (non-surgical/late postsurgical setting)

Cohen 2006The study evaluated regional/local techniques for analgesia

Elkaradawy 2012The study randomized a regional/local technique for analgesia. Gabapentin was administered for patients reporting moderate/severe pain

Essving 2009The study evaluated regional/local techniques for analgesia

Essving 2010The study evaluated regional/local techniques for analgesia

Fassoulaki 2000The intervention consisted of a topical intervention that is out of the scope of the review

Fassoulaki 2005This study combines a systemic analgesic (gabapentin) and topical analgesia. It is not possible to 'weight' the effectiveness of each intervention due to methodological issues

Fassoulaki 2006Patients were followed for less than 3 months

Fassoulaki 2007Patients were followed for less than 3 months

Fransen 2004This is the publication of a protocol

Guan 2005The study reported pain scores in the short term, only; for the long-term follow-up, the study reported range of motion

Gupta 2006The study evaluated regional/local techniques for analgesia

Harding 1991The study used a population out of the scope of the review (non-surgical/late postsurgical setting)

Hartrick 2011Patients were followed for less than 3 months

Honigmann 2007The study evaluated regional/local techniques for analgesia

Huse 2001Cross-over study that explored the impact of morphine sulfate in pain scores and sensory findings. Patients included were already amputated

Jaeger 1992Cross-over study

Jirarattanaphochai 2007The study evaluated regional/local techniques for analgesia

Kadic 2009The study evaluated regional/local techniques for analgesia

Kamencic 2008The study used a population out of the scope of the review (non-surgical/late postsurgical setting)

Kampe 2003The study evaluated regional/local techniques for analgesia

Katz 2004The study evaluated regional/local techniques for analgesia

Kim 2011Patients were followed for less than 3 months

Kollender 2008The study reported outcomes in the acute setting only

Koninckx 2008The study used a population out of the scope of the review (non-surgical/late postsurgical setting)

Lambert 2001The study evaluated regional/local techniques for analgesia

Lampl 2002The study used a population out of the scope of the review (non-surgical/late postsurgical setting)

Lavand'homme 2005The study has no placebo group

Lynch 2003The study used a population out of the scope of the review (non-surgical/late postsurgical setting)

Maier 2003Not preventive study; pain is already established

Martin 2008The study evaluated regional/local techniques for analgesia

Morin 2005The study evaluated regional/local techniques for analgesia

Nehler 2007The study used a population out of the scope of the review (non-surgical/late postsurgical setting)

Nesher 2008The study reported outcomes in the acute setting only

Nesher 2009The study reported outcomes in the acute setting only

Nikolajsen 1997The study evaluated regional/local techniques for analgesia

Nikolajsen 2000Not preventive study; pain is already established

Nissman 2008Patients were followed up for less than 3 months

Obata 1999The study evaluated regional/local techniques for analgesia

Parker 2006The study used a population out of the scope of the review (non-surgical/late postsurgical setting)

Perniola 2009The study evaluated regional/local techniques for analgesia

Reuben 2004Retracted publication

Reuben 2005Retracted publication

Reuben 2006Retracted publication

Reuben 2007Retracted publication

Reuben 2008Retracted publication

Rhodes 1988The study used a population out of the scope of the review (non-surgical/late postsurgical setting)

Ryu 2011The study evaluated regional/local techniques for analgesia

Salengros 2010The study is not placebo controlled

Sanders 2009The study evaluated regional/local techniques for analgesia

Senturk 2002The study evaluated regional/local techniques for analgesia

Sesti 2007The study used a population out of the scope of the review (non-surgical/late postsurgical setting)

Singh 2007The study evaluated regional/local techniques for analgesia

Solak 2007Not preventive study; pain is already established

Tramer 1996Patients were followed up for less than 3 months

Wai 2010The study evaluated the local administration of morphine, this review is focused in the impact of systemic analgesia

Waikakul 1999Open label trial

White 2007Patients were followed up for less than 3 months

Wu 2008Not preventive study; pain is already established

 
Characteristics of studies awaiting assessment [ordered by study ID]
Bilgen 2012

MethodsDouble blind, randomized trial

ParticipantsOne hundred and forty term pregnant women undergoing elective Cesarean delivery

InterventionsParticipants were randomized into four groups (N=35 each), placebo (0.9% normal saline), ketamine 0.25, 0.5, or 1 mg kg(-1) intravenously

OutcomesPatients were evaluated for persistent postoperative pain at 2 weeks, 1 and 6 months, and 1 year.

Notes

Cohen 2013

MethodsMulticenter, randomized, controlled trial

ParticipantsSeventy-seven patients undergoing inguinal hernia surgery

InterventionsSubcutaneous etanercept 50 mg administered 90 minutes before surgery vs. saline

OutcomesThe primary outcome measure was a 24-hour numerical rating scale pain score. Secondary outcome measures were postanesthesia care unit pain scores, 24-hour opioid requirements, time to first analgesic, and pain scores recorded at 1 month, 3 months, 6 months, and 12 months.

Notes

Fassoulaki 2012

MethodsRandomised controlled trial.

ParticipantsEighty patients scheduled for abdominal hysterectomy or myomectomy

InterventionsThe pregabalin group received 150 mg of pregabalin 8-hourly, starting on the afternoon before surgery and continued until the fifth postoperative day. The control group was similarly treated, but received placebo capsules instead.

OutcomesOne and 3 months postoperatively patients were interviewed for the presence of pain and analgesic needs due to surgery.

Notes

Martinez 2013

MethodsRandomized, double-blind, controlled study.

ParticipantsOne hundred patients undergoing scheduled lumbar discectomy

InterventionsThe minocycline group received 100mg minocycline orally, twice daily, beginning the evening before surgery and continuing for 8days.

OutcomesThe primary outcome was the change in lower limb pain intensity at rest between baseline and 3months. Secondary outcomes were pain intensity on movement, the incidence of persistent pain and chronic neuropathic pain, back pain intensity at rest and on movement, and changes in Neuropathic Pain Symptom Inventory, Brief Pain Inventory, and Roland-Morris scores at 3months.

Notes

Mendola 2012

MethodsRandomized, double-blind study.

ParticipantsSixty-six patients undergoing thoracotomy

InterventionsThirty-three patients received an i.v. infusion of S(+)-ketamine (Group S(+)K) for 60 hours and 33 patients received i.v. placebo (Group PLAC)

OutcomesNeuropathic Pain Symptom Inventory (NPSI) was evaluated at 1, 3 and 6 months.

Notes

NCT00224588

MethodsRandomized, double-blind, clinical trial

ParticipantsInclusion criteria: patients eligible for thoracotomy or pneumectomy

InterventionsDrug: Ketamine

OutcomesPrimary outcome measures: post thoracotomy pain at 2 months assessed using a french equivalent of the McGill Pain score and pain area measurements. Secondary outcome measures: Analogic pain scores at rest and after coughing

NotesThis study has been completed.

Short 2012

MethodsRandomized, double-blind, placebo-controlled dose-finding trial.

ParticipantsOne hundred and thirty-two women undergoing elective cesarean delivery

InterventionsParticipants were randomized into 3 groups to receive 300 or 600 mg oral gabapentin, or placebo, 1 hour before surgery.

OutcomesThe primary outcome was pain on movement at 24 hours. Secondary outcomes included satisfaction with analgesia, supplemental opioid consumption, lactation difficulties, neonatal outcomes, maternal sedation, and other adverse effects. Three months after delivery, patients were contacted for assessment of chronic pain.

Notes

 
Characteristics of ongoing studies [ordered by study ID]
NCT00129597

Trial name or titleEffect of Ketalar to Prevent Postoperative Chronic Pain After Mastectomy

MethodsRandomized, double-blind, clinical trial

ParticipantsAdult Patients (18-80), ASA I-II

Exclusion criteria: heart, hepatic or renal failure; allergy to study medications; psychiatric disease; chronic antalgic treatment

InterventionsKetalar (further information is unclear)

OutcomesPrimary outcome measures: pain intensity 3 months after mastectomy
Secondary outcome measures: impact on life quality; area of hyperalgesia

Starting dateDecember 2004

Contact informationVincent, PIRIOU, MD

NotesThe recruitment status of this study is unknown because the information has not been verified recently. Verified March 2007 by Hospices Civils de Lyon. Recruitment status was active, not recruiting

NCT00442546

Trial name or titleEfficacy And Safety Of Pregabalin For Pain Following Total Knee Replacement

MethodsRandomized, double-blind, clinical trial

ParticipantsInclusion criteria: Adult patients (ASA I-III)with osteoarthritis (OA) undergoing elective primary TKA under regional anesthesia (neuroaxial with or without peripheral nerve block)

Exclusion criteria: bilateral procedure or revision; subjects with chronic inflammatory conditions or any other chronic pain disorder

InterventionsPregabalin 150 mg/day, 300 mg/day or placebo

OutcomesPrimary Outcome Measures: Subject Reported Worst 0-10 Pain Score in Daily Diaries Using the Worst Pain Item of the Modified Brief Pain Inventory - Short Form (m-BPI-sf)

Long term Secondary Outcome Measures (at 3 & 6 months): Pain Interference Index Score as Measured by the m-BPI-sf; Pain Interference With Relations With People; Pain Interference With Enjoyment of Life; pain Interference With General Activity; pain Interference With Mood; Pain Interference With Walking Ability; pain Interference With Normal Work; Pain Interference With Sleep: number of Subjects With Persistent Pain Based on 11-Point Verbal Rating Scale (VRS); Neuropathic Pain Symptom Inventory (NPSI).

Starting dateMay 2007

Contact informationPfizer CT.gov Call Center

NotesThis study has been completed (First Received on March 1, 2007. Last Updated on February 15, 2011) 

NCT00468845

Trial name or titleStudy Of The Efficacy And Safety Of Pregabalin Compared To Placebo For Treatment Of Post-Surgical Pain From Hysterectomy

MethodsRandomized, double-blind, clinical trial

ParticipantsPatients (ASA I-II)undergoing elective total abdominal hysterectomy using a transverse incision with or without bilateral salpingo-oophorectomy. The subject is expected to remain at the hospital (or intermediate care facility) for a minimum of 2 days following surgery; Exclusion Criteria: vaginal hysterectomy; use of nerve block, spinal anesthesia or epidural anesthesia for post-surgical pain control; Subjects who have been using any opioid medications 2 weeks or more continuously within 3 months prior to the screening visit; NSAIDs users.

InterventionsPregabalin (Lyrica) 150 mg/day, 300 mg/day double-blind or matched placebos

OutcomesPrimary Outcome Measures: Worst Pain Using the Modified Brief Pain Inventory at day POP 2. Secondary Long-term Outcome Measures: Incidence of Chronic Post-operative Pain [ Time Frame: 3 and 6 Months PS ]Chronic post-operative pain as a result of abdominal hysterectomy as reported by participants on PS questionnaire of pain within last 24 hours in area affected by surgery.

Starting dateJune 2007

Contact informationPfizer

NotesThis study has been completed. First received on May 1, 2007. Last updated on June 7, 2011

NCT00551135

Trial name or titleSurgical Pain After Inguinal Hernia Repair (SPAIHR)

MethodsRandomized, double-blind, clinical trial

ParticipantsInclusion criteria: patients undergoing primary open unilateral inguinal herniorrhaphy (hernia repair), using mesh Lichtenstein surgery procedure and under general anesthesia; patients must be able to use and tolerate non-steroidal anti-inflammatory drugs (such as naproxen), tramadol, oxycodone, and acetaminophen/paracetamol for pain control after surgery.

Exclusion criteria: emergency surgery; use of nerve block or spinal/epidural/paravertebral anesthesia; subjects that are not allowed to receive the anesthesia agents indicated per protocol and general anesthesia.

InterventionsPregabalin 25 mg BID, or 75 mg BID or 150 mg BID or placebo

OutcomesPrimary outcome measures: Modified Brief Pain Inventory-Short Form (mBPI-sf): Worst Pain 24 Hours Post Surgery. A self-administered 11-point Likert rating scale to rate pain in the past 24 hours.
Secondary long-term outcome measures (3 & 6 months after surgery): Number of participants who reported surgery-related pain at assessment; Pain Severity Index Score and Pain Interference Index Score on the Modified Brief Pain Inventory-Short Form (mBPI-sf); Total Score and Subscale Scores Using the Neuropathic Pain Symptom Inventory (NPSI).

Starting dateJanuary 2008

Contact informationPfizer

NotesThis study has been completed. First Received on October 26, 2007. Last Updated on June 8, 2010  

NCT00583869

Trial name or titleRole of Pregabalin in Treatment of Post-Op Pain in Fracture Patients (LYRICA)

MethodsRandomized, double-blind, clinical trial

ParticipantsInclusion criteria: patients (19-70) with fractures requiring operative treatment during a single operative episode

Exclusion criteria: history of opioid abuse/misuse; contraindications to pregabalin or narcotic analgesics; closed head injury; psychiatric illness requiring medical treatment; surgery for other injuries (splenectomy, etc); history of seizures requiring current anticonvulsant therapy.

InterventionsPlacebo group: Two hours before surgery, patients will receive 75mg of pregabalin. Patients will be placed on a patient-controlled anesthesia pump (PCA) for 24 hours. On post-operative day one, the patients will be switched to oral oxycodone as needed with supplementation with IV Demerol for breakthrough pain. In addition, patients will receive a placebo PO BID or pregabalin 75 mg or pregabalin 150 mg beginning on the day of surgery until discharge.Upon discharge, the patient will be given study medication (placebo PO BID or pregabalins). Rescue medications will be allowed during the study (including post-operative and outpatient periods). Outpatient rescue medications will consist of hydrocodone/APAP 7.5mg PO Q6H PRN.

OutcomesPrimary outcome measures: Amount of pain medication in morphine equivalent units used during the hospitalization
Secondary outcome measures: pain scores at 3 months

Starting dateMay 2007

Contact informationDavid A. Volgas, MD, Associate Professor of Surgery, The University of Alabama at Birmingham

NotesThis study is ongoing, but not recruiting participants. First received on December 21, 2007. Last updated on September 15, 2010

NCT00618423

Trial name or titleThe Effect of Perioperative Ketamine on Acute and Chronic Pain After Major Back Surgery (KetaDol)

MethodsRandomized, double-blind, clinical trial

ParticipantsInclusion criteria: Adults, ASA I-III, undergoing back surgery (laminectomy, lumbar arthrodesis (Posterior Lumbar Interbody Fusion - PLIF, Transforaminal Lumbar Interboby Fusion - TLIF, Postero-lateral Fusion, semi-rigid fixation. Exclusion Criteria: heart disease, glaucoma, allergy to study drugs, dementia, failed back surgery syndrome, postraumatic paraplegia.

Interventions50 ml syringes provided by the HUG pharmacy will contain 1% ketamine or 0.9% NaCl. After induction and before start of surgery, patients will receive an intravenous bolus of 0.025 ml/kg of the study solution (corresponding to 0.25 mg/kg ketamine). Maintenance will be with a syringe driver at a rate of 0.025 ml/kg/h (corresponding to 0.25 mg/kg/h ketamine) until one hour before the end of surgery, and will then be decreased to a rate of 0.01 ml/kg/h (corresponding to 0.1 mg/kg/h ketamine) throughout the stay in the recovery room (usually 2 to 3 hours). The infusion will be stopped when the patient leaves the recovery room.

OutcomesPrimary outcome measures: 6 and 12 months effect of perioperative intravenous low-dose ketamine on chronic neuropathic pain in patients undergoing major back surgery.
Secondary long-term outcome measures: short-term (during hospitalisation) effect of perioperative intravenous low-dose ketamine in patients undergoing major back surgery: tolerability and safety, opioid-sparing effect, pain intensity, morphine-related adverse effects. To study psychosocial factors that may be involved in the perception of acute and chronic postoperative pain in patients with or without chronic back pain undergoing back surgery.

Starting dateOctober 2007

Contact informationStudy Chair: Martin Tramèr, Prof, MD, PhD. Christoph Czarnetzki, Responsable Investigator, University Hospital, Geneva

NotesThis study is ongoing, but not recruiting participants. First received on February 6, 2008. Last updated on April 3, 2012  

NCT00631891

Trial name or titlePregabalin in Treating Pain in Women Undergoing Mastectomy or Lumpectomy

MethodsRandomized, double-blind, clinical trial

ParticipantsPatients (ASA I-III) undergoing unilateral modified radical mastectomy or lumpectomy with axillary node dissection. Exclusion criteria: allergy to study drugs, drug/alcohol abuse; kidney failure; concurrent use of other analgesics.

InterventionsOral placebo or pregabalin 1-2 hours prior to surgery, at 12 hours after surgery, and then twice daily for 14 days

OutcomesPrimary outcome measures: pain scores at 3 months; PCA morphine consumption; side effects profile; and modified Brief Pain Inventory-short form

Starting dateDecember 2006

Contact informationBabatunde Ogunnaike, Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas

NotesThe recruitment status of this study is unknown because the information has not been verified recently. Verified May 2009 by National Cancer Institute (NCI). Recruitment status was: Recruiting

NCT00663962

Trial name or titlePregabalin and Post-thoracotomy Pain

MethodsRandomized, double-blind, clinical trial

ParticipantsInclusion criteria: patients (18-75; ASA I-III)undergoing elective thoracotomy (ET) or video assisted thoracotomy (VAT).

Exclusion criteria: intolerance to study drugs; Contraindication to thoracic epidural placement; Renal insufficiency (serum creatinine > 1.5 x upper limit of normal); Body Mass Index > 40; surgery extending to the chest wall; alcohol abuse; chronic pain/analgesic use; History of congestive heart failure; Major psychiatric disorder; Insufficient safety data in a specific patient population; Pregnant or breastfeeding.

InterventionsPregabalin 150mg or 300 mg or placebo administered 1 hour prior to surgery and 12 hours after surgery, then continued BID until day 7 post-op

OutcomesPrimary outcome measures: The primary outcome measure for the final study will be the incidence of CPTPS at 2 months. [Time Frame: 2, 4, and 6 months]

Starting dateApril 2008

Contact informationDr Jorge Enrique Zamora, Department of Anesthesiology, Queen's University

NotesThe recruitment status of this study is unknown because the information has not been verified recently. Verified September 2009 by Queen's University. Recruitment status was active, not recruiting

NCT00762099

Trial name or titlePerioperative Pregabalin Use, Rehabilitation, Pain Outcomes and Anxiety Following Hip Surgery (RCT)

MethodsRandomized, double-blind, clinical trial

ParticipantsInclusion criteria: Patients (18-75), ASA I-III undergoing total hip arthroplasty. Exclusion criteria: allergy to study drugs; drug/alcohol/opioid abuse; rheumatoid arthritis; psychiatric disorders; renal failure; obesity.

InterventionsPre-operative pregabalin 150 mg or placebo plus post-operative dose 75 mg bid or placebo

OutcomesMovement-evoked pain scores at 6 weeks and 3 months post surgery

Starting dateMay 2009

Contact informationColin McCartney, MD. colin.mccartney@sunnybrook.ca

NotesThis study is currently recruiting participants. Verified April 2011 by Sunnybrook Health Sciences Centre

NCT00852683

Trial name or titleThe Effects of Peri-Operative Pregabalin on Post-Operative Pain Following Breast Cancer Surgery With Axillary Node Dissection: A Pilot Study

MethodsRandomized, double-blind, clinical trial

ParticipantsInclusion criteria: patients (18-60), ASA I-III undergoing breast surgery with axillary dissection for the treatment of breast cancer.

Exclusion criteria: persons with a history of allergy to gabapentin or pregabalin, morphine, NSAIDs, acetaminophen or oxycodone; pregnancy; Body Mass Index >40; liver or renal failure; chronic opioid users (30 mg per day of morphine equivalent); gabapentin or pregabalin users within 3 months of surgery; persons with a history of drug abuse.

InterventionsParticipants will receive pregabalin (75 mg BID) or placebo (sugar pills) for BID for 14 days starting 1 hour before surgery

OutcomesPrimary Outcome Measures: numeric rating pain Score at rest and with movement 24 hours after surgery.
Secondary Outcome Measures: Incidence of chronic post-mastectomy pain at 3 months defined as persistent pain or discomfort not present prior to surgery and not present as a result of new or recurrent tumour growth.

Starting dateMay 2008

Contact informationPeter MacDougall, MD. pcmacdou@gmail.com

NotesThis study is currently recruiting participants. Verified January 2009 by Capital District Health Authority, Canada

NCT00905437

Trial name or titleStudy To Investigate The Effectiveness Of Pregabalin For Management Of Patients Undergoing Total Hip Replacement

MethodsRandomized, double-blind, clinical trial

ParticipantsInclusion criteria: patients undergoing total primary or secondary hip replacement surgery performed under spinal anesthesia.

Exclusion criteria: revision surgery, hip replacement secondary to trauma; history of uncontrolled chronic disease or a concurrent clinically significant illness or medical condition, which in the Investigator's opinion, would contraindicate study participation or confound interpretation of the results.

InterventionsPlacebo or pregabalin 75 mg BID for 14 days

OutcomesPrimary outcome measures: O-10 Pain score on Movement obtained over postoperative Days 1-5.

Secondary long-term outcome measures: Incidence of neuropathic pain as detected using the ID Pain questionnaire 3 & 6 months following the surgery.

Starting dateNovember 2009

Contact informationPfizer

NotesThis study is currently recruiting participants. Verified April 2012 by Pfizer

NCT00967135

Trial name or titleEfficacy of Perioperative Pregabalin in Reducing the Incidence of Chronic Neuropathic Pain and Postthoracotomy Syndrome.

MethodsRandomized, double-blind, clinical trial

ParticipantsInclusion criteria: patients aged 18 to 80 years, ASA I-III, undergoing elective thoracotomy.

Exclusion criteria: contraindication to pregabalin or epidural technique; current use of opioids, NMDA receptor blockers, membrane stabilizing agents (lidocaine mesylates, flecainide) or topical coanalgesics (capsaicin cream, lidocaine patch); previous use of pregabalin or gabapentin; preexisting pain at the surgical site or any other chronic pain syndrome; creatinine clearance of less than 60 mL/min; previous thoracotomy; recent history of alcohol and/or drug abuse; known allergy to local anesthetics or hydromorphone.

InterventionsPregabalin 150 mg bid or matching placebos during 5 days, starting the days before surgery

OutcomesPrimary outcome measures: development of neuropathic pain and intensity of pain assessed using the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scale and Brief Pain Inventory questionnaire (BPI) at 3 months

Starting dateJune 2010

Contact informationCentre hospitalier de l'Université de Montréal (CHUM)

NotesThis study has been completed. First received on August 26, 2009. Last updated on April 11, 2012

NCT01022840

Trial name or titleThe Preemptive Analgetic Potency of Low Dose S-Ketamine (Miniket)

MethodsRandomized, double-blind, clinical trial

ParticipantsInclusion criteria: adult patients (ASA I-III) scheduled for major abdominal surgery, suitable for PCA, with acceptable compliance for pain monitoring.

Exclusion criteria: allergy to S-Ketamine, severe liver or kidney dysfunction, severe coronary disease, pregnancy, present or past psychotic disorders, addiction to alcohol or opioids.

Interventions3 groups: placebo as saline solution, low dose ketamine and high dose ketamine

OutcomesPrimary Outcome Measures: postoperative opioid consumption [Time Frame: 1 year]

Starting dateFebruary 2009

Contact informationAndreas Sandner-Kiesling, MD (andreas.sandner@medunigraz.at)

NotesThis study is currently recruiting participants. Verified February 2012 by Medical University of Graz

NCT01116583

Trial name or titleThe Effect of Gabapentin on Thoracic Epidural Analgesia Following Thoracotomy (GABATEA)

MethodsRandomized, double-blind, clinical trial

ParticipantsInclusion criteria: patients undergoing elective lung resection via thoracotomy, aged 18- 80 years.

Exclusion criteria: Inability to answer the detailed questionnaires on pain and quality of life; Psychiatric disease (ICD-10); Severe renal impairment (se-creatinin > 110 mmol/l); chronic opioid or anticonvulsant or antidepressant user; allergy to study drugs; user of antacids 24 hours before the intake of study medication; previous ipsilateral thoracotomy; chronic pain syndrome; acute pancreatitis; history of past or current alcohol and / or illegal substance abuse; history of gastric or duodenal ulcer; gastrointestinal obstruction; pregnancy.

InterventionsPreoperative gabapentin (1200 mg) or placebos plus postoperative increasing dose of gabapentin (600 - 1200 mg) or matching placebos up to the 5th day after surgery

OutcomesPrimary outcome measures: persistent postsurgical pain at 3, 6 & 12 months after surgery by Brief Pain Inventory and The McGill Pain Questionnaire. Persistent postoperative pain is measured both on a 11-point numeric pain rating scale and on a 10 cm visual analog scale (VAS). A score >=3 is considered as moderate pain.

Secondary long-term outcome measures: Health related quality of life measured at 3, 6 and 12 months.

Starting dateMay 2011

Contact informationHans K Pilegaard, MD, Chief Surgeon

NotesThis study is currently recruiting participants. Verified March 2012 by University of Aarhus

NCT01204242

Trial name or titleIV Lidocaine for Patients Undergoing Primary Breast Cancer Surgery: Effects on Postoperative Recovery and Cancer

MethodsRandomized, double-blind, clinical trial

ParticipantsInclusion criteria: patients aged 18 to 80 years, ASA I-III, scheduled for breast cancer mastectomy.

Exclusion criteria: allergy to study drugs, severe cardiovascular disease (myocardial infarction within 6 months), profoundly decreased left ventricular function (ejection fraction <40%) or high-grade arrhythmias, severe liver disease, renal impairment, or pregnancy.  

InterventionsSubjects will receive lidocaine up to 1.5mg/kg intravenously plus infusion of the study medication (containing lidocaine 8 mg/ml or placebo) for up to 2 hours in the recovery room.

OutcomesPrimary Outcome Measures: opioid consumption the first week after surgery.

Secondary long term Outcome Measures: chronic pain at 6 months after surgery; cancer recurrence at 5 years after surgery.

Starting dateAugust 2009

Contact informationMohammed Tiouririne, MD

NotesThis study is enrolling participants by invitation only. First Received on September 15, 2010.   Last Updated on August 9, 2011

NCT01243801

Trial name or titlePrevention of Persistent Postsurgical Pain After Thoracotomy

MethodsRandomized, double-blind, clinical trial

ParticipantsInclusion criteria: adult patients submitted to thoracotomy or mini-thoracotomy expected to be extubated in the operating room

Exclusion criteria: allergy or intolerance to study drugs; Chronic preoperative pain; Chronic opioid treatment; Drug addiction; Polyneuropathy; Ischemic cardiopathy; or Psychiatric disease

InterventionsBolus of epidural or intravenous ketamine during the induction of anesthesia plus infusion of ketamine the first 2 days after surgery. Postoperative analgesia: Epidural "Patient Controlled Analgesia" with ropivacaine and fentanyl. A Placebo Group will receive epidural "Patient Controlled Analgesia" with ropivacaine and fentanyl

OutcomesPrimary outcome measures: pain scores, Neuropathic Pain Symptoms Inventory, and Catastrophism Scale at 3 months and 6 months after surgery. Change from hyperalgesia peri-incisional area at 3 months and 6 months after surgery. Hyperalgesia measured with von Frey monofilaments, electronic von frey and electric brush around the surgical incision and in a separate area (thigh).
Secondary outcome measures: adverse effects: any time until 6 months.

Starting dateSeptember 2008

Contact informationBarcelona, Spain, 08036

Contact: Beatriz Tena     0034932275400 ext 5558  btena@clinic.ub.es

Principal Investigator: Beatriz Tena, MD    

NotesThis study is currently recruiting participants. Verified June 2011 by Hospital Clinic of Barcelona

NCT01296347

Trial name or titleLow Dose Peri-operative IV Ketamine for Chronic Post-surgery Pain Prevention

MethodsRandomized, double-blind, clinical trial

ParticipantsAdult patients undergoing either thoracotomy or video assisted thoracic surgery.

Exclusion criteria: history of previous chronic thoracic pain; neuropathic pain (whatever the site), existing at time of recruitment; pre-operative analgesic treatments with strong opioids or tricyclic antidepressants, venlafaxine, gabapentin, pregabalin, duloxetine, clonazepam or carbamazepine. Allergy to study drugs.

InterventionsIntravenous infusion of saline or ketamine running at 0.1mg/kg/hour, starting 10 minutes prior to surgery up to 96 hours in total. A loading dose of ketamine (0.1 mg per kg) will be administered.

OutcomesPrimary outcome measures: incidence of pain (0-10) at 6 weeks after surgery, brief Pain Inventory, and Leeds Assessment of Neuropathic Symptoms and Signs.
Secondary long-term outcome measures: analgesic consumption at 3, 6 and 12 months. Sensory testing at 6 months & 12 months. Incidence of pain (0-10) at 3, 6 and 12 months, Brief Pain Inventory, and Leeds Assessment of Neuropathic Symptoms and Signs.

Starting dateApril 2011

Contact informationContact: Gillian M Chumbley, BSc, PhD. gillian.chumbley@imperial.nhs.uk

NotesThis study is not yet open for participant recruitment. Verified January 2011 by Imperial College Healthcare NHS Trust

NCT01359059

Trial name or titlePre- Versus Post-incisional Pregabalin for Postoperative Pain Attenuation and Analgesics Spare in Orthopedic Oncologic Patients

MethodsRandomized, double-blind, clinical trial

ParticipantsInclusion criteria: ASA physical status I-III adult patients who will undergo bone with or without soft tissue cancer surgery type II and III under general or epidural anesthesia.

Exclusion criteria: allergy to study drugs; chronic pain; psychiatric disorders; chronic use of centrally acting drugs of any sort, pregnancy.

InterventionsPatients will receive 150 mg of pregabalin or placebo the evening before surgery and 1.5 hours before surgery and will undergo surgery under GA. A second cohort of patients will be randomized similarly but will undergo surgery under epidural analgesia. No other premedication will be administered to any patient. Post-operatively, patients who received preoperative pregabalin will be given placebo and vice versa at 2 hours after surgery. All patients will receive pregabalin 150 mg twice daily thereafter, BID postoperatively up to day 4.

OutcomesPrimary outcome measures: to assess the effects of the drug administered either pre-incisionally or post-incisionally on the immediate and late setting (1- and 3 months); pain scores will be measured again 2 years after surgery.

Starting dateJune 2011

Contact informationAvi A Weinbroum, Tel-Aviv Sourasky Medical Center

NotesThis study is not yet open for participant recruitment. Verified June 2011 by Tel-Aviv Sourasky Medical Center

NCT01391858

Trial name or titlePostoperative Pain and Morphine Consumption After Mastectomy - Lyrica

MethodsRandomized, double-blind, clinical trial

ParticipantsInclusion: 80 adult women (17 - 80) undergoing mastectomy. Exclusion criteria: those with known allergy to pregabalin or morphine and those with a history of alcohol abuse, chronic pain, history of daily intake of analgesics or steroids, and patients with impaired kidney function or diabetes mellitus.

InterventionsPregabalin 300 mg or matching placebos will be administered to each patient one to 2 hours before surgery followed by 150 mg BID during 2 weeks.

OutcomesPrimary outcome measures: opioid Requirement at 14 days; IV-PCA morphine for rescue pain management in the immediate postoperative period and oral opioids after discontinuation of IV-PCA. Secondary outcome measures: pain scores at 3 months.

Starting dateDecember 2006

Contact informationBABATUNDE OGUNNAIKE, MD, UT SOUTHWESTERN MEDICAL CENTER

NotesThe recruitment status of this study is unknown because the information has not been verified recently. Verified December 2009 by University of Texas Southwestern Medical Center. Recruitment status was active, not recruiting

NCT01480765

Trial name or titlePreventing Pain After Heart Surgery

MethodsRandomized, double-blind, clinical trial

ParticipantsInclusion criteria: Patients aged 18-80, undergoing sternotomy for elective cardiac surgery.

Exclusion criteria: Previous sternotomy; preoperative renal failure; history of chronic non-anginal pain; chronic pain medication other than paracetamol and NSAIDs, concurrent use of oxycodone, lorazepam, or ethanol; concurrent use of any drugs for neuropathic pain (e.g. antiepileptics, antidepressants); allergy to study drugs; or pregnancy.

InterventionsPregabalin 150mg (2 hours) or matching placebos preoperatively and bid for 10 days, followed by dose reduction to 75mg twice daily for 2 days and finally to 50 mg twice daily for 2 days Drug; a third group will receive a placebo controlled Ketamine infusion 0.1mg/kg/hr for 48 hours postoperatively.

OutcomesPrimary outcome measures: peri-incisional pain scores at 3 months, at rest and following 3 maximal coughs.
Secondary long-term outcome measures: Neuropathic pain score at 3 months using the Short form Leeds Assessment of Neuropathic Symptoms and Signs; Quality of Life at 3 months; Preoperative and postoperative sensory test by Pressure algometry, tactile and pain detection thresholds with mechanical static stimulus using von Frey hairs and dynamic assessment of spatial and temporal summation.

Starting dateNovember 2011

Contact informationSibtain Anwar, MA MB FRCA. sibtain.anwar@bartsandthelondon.nhs.uk

NotesThis study is currently recruiting participants. Verified March 2012 by Barts & The London NHS Trust

 
Comparison 1. Ketamine versus placebo comparisons

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Incidence of any pain at 3 months (all studies)5384Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.61, 1.11]

    1.1 Breast Surgery
130Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.79, 1.69]

    1.2 Hemorrhoidectomy
172Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.15, 6.72]

    1.3 Orthopedic Surgery
2238Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.54, 1.32]

    1.4 Thoracotomy
144Risk Ratio (M-H, Fixed, 95% CI)0.5 [0.25, 1.00]

 2 Incidence of any pain at 3 months (drug administration ≤ 24 hours)3249Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.69, 1.35]

    2.1 Breast Surgery
130Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.79, 1.69]

    2.2 Hemorrhoidectomy
172Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.15, 6.72]

    2.3 Orthopedic Surgery
1147Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.55, 1.41]

 3 Incidence of any pain at 3 months (drug administration > 24 hours)2135Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.28, 1.00]

    3.1 Orthopedic Surgery
191Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.15, 2.71]

    3.2 Thoracotomy
144Risk Ratio (M-H, Fixed, 95% CI)0.5 [0.25, 1.00]

 4 Incidence of any pain at 4 months169Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.48, 1.46]

 5 Incidence of any pain at 6 months (all studies)8516Risk Ratio (M-H, Fixed, 95% CI)0.63 [0.47, 0.83]

    5.1 Abdominal and/or pelvic surgery
2164Risk Ratio (M-H, Fixed, 95% CI)0.40 [0.19, 0.88]

    5.2 Amputation
132Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.35, 1.23]

    5.3 Breast surgery
186Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.47, 1.60]

    5.4 Orthopedic surgery
3190Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.40, 1.06]

    5.5 Thoracotomy
144Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.25, 1.21]

 6 Incidence of any pain at 6 months (drug administration ≤ 24 hours)4318Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.36, 0.83]

    6.1 Abdominal and/or pelvic surgery
2164Risk Ratio (M-H, Fixed, 95% CI)0.40 [0.19, 0.88]

    6.2 Orthopedic Surgery
2154Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.39, 1.04]

 7 Incidence of any pain at 6 months (drug administration > 24 hours)4198Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.49, 1.06]

    7.1 Amputation
132Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.35, 1.23]

    7.2 Breast Surgery
186Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.47, 1.60]

    7.3 Orthopedic Surgery
136Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.08, 16.52]

    7.4 Thoracotomy
144Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.25, 1.21]

 8 Incidence of Moderate or severe pain at 6 months3259Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.26, 0.95]

    8.1 Amputation
131Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.32, 3.52]

    8.2 Breast Surgery
186Risk Ratio (M-H, Fixed, 95% CI)0.48 [0.18, 1.32]

    8.3 Total hip arthroplasty
1142Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.08, 1.02]

 9 Incidence of any pain at 12 months2104Risk Ratio (M-H, Fixed, 95% CI)0.26 [0.06, 1.15]

 
Comparison 2. Gabapentin versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Incidence of any pain at 3 months (all studies)5280Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.80, 1.21]

    1.1 Amputation (phantom limb pain)
138Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.61, 2.03]

    1.2 Breast Surgery
146Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.56, 1.56]

    1.3 Caesarean section
136Risk Ratio (M-H, Fixed, 95% CI)0.63 [0.13, 2.99]

    1.4 Cardiac Surgery
140Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.36, 1.68]

    1.5 Thoracotomy
1120Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.83, 1.34]

 2 Incidence of any pain at 3 months (drug administration ≤ 24 hours)2156Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.79, 1.30]

    2.1 Caesarean section
136Risk Ratio (M-H, Fixed, 95% CI)0.63 [0.13, 2.99]

    2.2 Thoracotomy
1120Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.83, 1.34]

 3 Incidence of any pain at 3 months (drug administration > 24 hours)3124Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.66, 1.34]

    3.1 Amputation (phantom limb pain)
138Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.61, 2.03]

    3.2 Breast surgery
146Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.56, 1.56]

    3.3 Cardiac surgery
140Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.36, 1.68]

 4 Incidence of any pain at 6 months2116Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.72, 1.68]

    4.1 Amputation (phantom limb pain)
134Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.64, 1.97]

    4.2 Total hip arthroplasty
182Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.60, 1.98]

 5 Mean Pain Score at 6 months (continuous data)1100Mean Difference (IV, Fixed, 95% CI)-1.0 [-5.16, 3.16]

 
Comparison 3. Pregabalin versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Incidence of any pain at 3 months follow up (all studies)4439Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.51, 0.95]

    1.1 Cardiac surgery
157Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.02, 1.04]

    1.2 Total Knee Arthroplasty
1228Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.40, 1.02]

    1.3 Spine Surgery
160Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.63, 1.81]

    1.4 Thyroidectomy
194Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.38, 1.58]

 2 Incidence of any pain at 3 months (drug administration ≤ 24 hours)194Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.38, 1.58]

    2.1 Thyroidectomy
194Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.38, 1.58]

 3 Incidence of any pain at 3 months (drug administration > 24 hours)3345Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.48, 0.96]

    3.1 Cardiac Surgery
157Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.02, 1.04]

    3.2 Total knee arthroplasty
1228Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.40, 1.02]

    3.3 Spine surgery
160Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.63, 1.81]

 4 Incidence of any pain at 6 months1228Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.30, 0.93]

    4.1 Total Knee Arthroplasty
1228Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.30, 0.93]

 5 Incidence of moderate to severe pain at 3 months1228Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.20, 0.94]

    5.1 Total Knee Arthroplasty
1228Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.20, 0.94]

 6 Incidence of moderate to severe pain at 6 months1228Risk Ratio (M-H, Fixed, 95% CI)0.23 [0.07, 0.80]

    6.1 Total knee arthroplasty
1228Risk Ratio (M-H, Fixed, 95% CI)0.23 [0.07, 0.80]

 7 Incidence of any pain at 12 months follow up160Risk Ratio (M-H, Fixed, 95% CI)0.63 [0.23, 1.69]

    7.1 Major spinal surgery
160Risk Ratio (M-H, Fixed, 95% CI)0.63 [0.23, 1.69]

 
Comparison 4. Venlafaxine versus placebo comparisons

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mean Pain Score at 6 months (continuous data)1100Mean Difference (IV, Fixed, 95% CI)-10.0 [-12.85, -7.15]

 
Table 1. Ketamine trials

Study IDSurgeryPreoperative Dose (μg/kg)Intraoperative Dose (μg/kg/h)Postoperative Dose (μg/kg/h)Cumulative dose (μg/kg)

Chaparro 2010Breast surgery420200none420 + (200 x 2h) = 820*

Crousier 2008Breast surgery500250none500 + (250 x 1.63h) = 908*

De Kock 2001Rectal carcinoma resection250125none250 + (125 X 4.3h) = 772*

De Kock 2001Rectal carcinoma resection500250none500 + (250 X 4.38h) = 1,595*

Duale 2009Thoracotomy100010001000 for 24h3,000*

Dullenkopf 2009Orthopedic surgery150nonenone150

Dullenkopf 2009Orthopedic surgery500nonenone500

Hayes 2004Amputation500150 for 72h11,300





Katz 2004aRadical prostatectomy200175 in 70 minutesnone375

Katz 2004aRadical prostatectomyNone200 + 175 in 70 minutesnone375

Malek 2006Breast surgeryNone1,000/day for 48 hours2,000





Perrin 2009Total knee arthroplasty500240none500 + (4x125.4)= 1,001.6*

Remerand 2009Total hip arthroplasty500120 for 24h3,380*





Sen 2009aHysterectomy30050none300 + (50 x 1.25h)= 362.5*

Spreng 2010Hemorrhoidectomy350300none350+ (300 x 0.33)= 451.5*

Suzuki 2006Thoracotomynone50 for 72h3,600*





Sveticic 2008Orthopedic surgerynonenone1.5 mg**1,198***

 *Calculation based on reported anesthesia duration.
** 1.5 mg of ketamine per each PCA opioid bolus.
***Calculation based on ketamine consumption and timing of administration.
 
Table 2. Gabapentin trials

Study IDSurgeryPreoperative Dose (mg)Postoperative Dose (mg/day)Cumulative Dose (mg)Cumulative Days

Amr 2010Breast surgery3003003,00010

Brogly 2008Thyroidectomy1,200none1,200single dose

Clarke 2009Total hip arthroplasty600none600single dose

Clarke 2009Total hip arthroplastynone600600single dose

Fassoulaki 2002Breast surgery800120012,00010

Kinney 2011Thoracotomy600none600single dose

Moore 2011Caesarean600none600single dose

Nikolajsen 2006AmputationNone300 to 2,40075,60030

Sen 2009aHysterectomy1,200none1,200single dose

Sen 2009Inguinal herniorrhaphy1,200none1,200single dose

Ucak 2011Cardiac surgery1,2001,2003,6002

 
Table 3. Pregabalin trials

Study IDSurgeryPreoperative Dose (mg)Postoperative Dose (mg/day)Cumulative Dose (mg)Cumulative Days

Burke 2010Spine surgery3003006001

Buvanendran 2010Total knee arthroplasty300300 to 1003,80014

Gianesello 2012Spine surgery3003009002

Kim 2010Thyroidectomy1501503001

Pesonen 2011Cardiac surgery1501507505

 
Table 4. Other drugs

Study IDDrugSurgeryPreoperative Dose (mg)Postoperative Dose (mg/day)Cumulative Dose (mg)Cumulative Days

Amr 2010VenlafaxineMastectomy37.537.537510 days

Bergeron 2009DexamethasoneHip arthroplasty40none40Single dose

Romundstad 2006Methyl-prednisoloneBreast augmentation125 mgnone125Single dose

Weis 2006HydrocortisoneCardiac surgery100240 to 305504 days

Chan 2011Nitrous oxideNumerousIntraoperative 70%N.A.Intraoperative






Eisenberg 2007;AmantadineMastectomy1002002,80014 days

Ilkjaer 2000Dextro-methorphanHysterectomy750none750Single dose

Schley 2007MemantineAmputationnone10 to 4063028 days

Grigoras 2012LidocaineBreast surgeryBolus 1.5 mg/kg + 1.5 mg/kg/hour up to the first hour after surgery.




Fassoulaki 2001MexiletineMastectomy2004002,4006 days

Fassoulaki 2002MexiletineBreast surgery4006006,00010 days

Fransen 2006IbuprofenHip arthroplastyNone1,20016,80014 days

Lakdja 1997IbuprofenMastectomy4001,6002,0002 days

Romundstad 2006ParecoxibBreast augmentation40 mgnone40 mgSingle dose

Karanikolas 2011FentanylAmputation58.3 mcg/h54.5 mcg/hVariable2 days