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Prevention of Persistent Postsurgical Pain After Thoracotomy

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ClinicalTrials.gov Identifier: NCT01243801
Recruitment Status : Completed
First Posted : November 19, 2010
Last Update Posted : March 23, 2015
Sponsor:
Information provided by (Responsible Party):
Beatriz Tena, Hospital Clinic of Barcelona

Tracking Information
First Submitted Date  ICMJE November 15, 2010
First Posted Date  ICMJE November 19, 2010
Last Update Posted Date March 23, 2015
Study Start Date  ICMJE September 2008
Actual Primary Completion Date October 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 18, 2010)
  • Change from subjective pain scales: Visual Analogical Scale, Neuropathic Pain Symptoms Inventory, Catastrophism Scale [ Time Frame: -1day, 3 days, 7 days, 3 months, 6 months ]
    Pain measured with these subjective scales are assessed preoperatively (-1 day) and 3, 7 days, 3 and 6 months after surgery
  • Change from hyperalgesia periincisional area [ Time Frame: -1day, 3day,7day,3 months, 6 months ]
    Hyperalgesia is measured with von Frey monofilaments, electronic von frey and electric brush around the surgical incision and in a separate area (thigh)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 18, 2010)
Adverse effects [ Time Frame: any time until 6 months ]
Any adverse effects related to the use of ketamine (cognitive effects, visual effects, haemodynamic effects or sedation effects)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Prevention of Persistent Postsurgical Pain After Thoracotomy
Official Title  ICMJE Phase 4 Study of Prevention of Persistent Postsurgical Pain After Thoracotomy Using Ketamine
Brief Summary Postthoracotomy acute pain is followed by persistent postsurgical pain in 20-30% of the patients, defined as pain that lasts more than 3-6 months after surgery. Acute pain and hyperalgesia around the surgical wound are some of the risk factors associated to the development of chronic pain. Ketamine, as a NMDA antagonist mainly at spinal level, might reduce periincisional hyperalgesia and persistent postsurgical pain after thoracotomy. Therefore, the investigators hypothesized that continuous ketamine infusion at subanesthetic dose would potentiate epidural ropivacaine and fentanyl-induced analgesia after thoracotomy, reduce periincisional hyperalgesia and long-term postoperative pain. To test these hypothesis, the investigators administered a low dose of intravenous ketamine or epidural ketamine or placebo to patients who received an epidural infusion of ropivacaine and fentanyl for postthoracotomy pain.
Detailed Description

Chronic pain is a frequent complication after common surgical procedures such as amputation, mastectomy or thoracotomy. A rate between 20 and 60% of patients undergoing thoracotomy are reported to develop long-lasting pain.

The causes of chronic pain after surgery are not fully known but several risk factors have been identified including pre and postoperative pain, nerve injury during surgery and physicological and genetic factors. The observed symptoms of allodynia and hyperalgesia in the periincisional area and evidence of intercostal nerve injury due to rib retraction during surgery suggest a neuropathic aetiology.

Excitatory neurotransmitters, acting through N-metil-aspartate receptor, have been recently postulated to play an important role in the development and maintenance of pathologic pain states. In experimental pain research, NMDA receptor antagonists reduced wind-up and central sensitization. Ketamine is one of the few NMDA antagonists available in clinical practice that, administered at subanesthetic doses, would inhibit the spinal processing of nociceptive input.

It has been proposed that analgesic drugs might more adequately prevent central sensitization when administered during the entire period of high-intensity noxious stimulation.

Therefore, the investigators hypothesized that continuous ketamine infusion would potentiate epidural ropivacaine and fentanyl-induced analgesia after posterolateral thoracotomy or minithoracotomy, reduce periincisional hyperalgesia and long-term postoperative pain. To test these hypothesis, the investigators administered a low dose of intravenous or epidural ketamine or placebo to patients who received an epidural infusion of ropivacaine and fentanyl for postthoracotomy pain.

The Institutional Review Board of the hospital approved this study, and each patient gave written informed consent. The investigators planned to enroll 90 patients who were scheduled to undergo posterolateral thoracotomy or minithoracotomy in this double-blind, controlled, randomized study. Patients who met the inclusion and exclusion criteria would be included and assigned to one of the three groups by a computer-generated schedule. Patients, nurses in charge of postoperative care, and staff members, who inform the patient performed analgesia, and collected data are blinded to the group.

The day before surgery patients are instructed on the use of Patient Controlled Analgesia pump, Visual Analogue Scale (VAS) and the Quantitative Sensory Testing. Subjective tests (VAS, neuropathic pain symptom inventory, pain catastrophizing scale) and QST are also performed the day before surgery.

Anesthetic management is standardized to all study patients. Premedication with sublingual diazepam (5-10 mg) is administered 2 hours before surgery. A thoracic epidural catheter is placed before induction through the T7-8 interspace. General anesthesia is induced by fentanyl (3 mcg/kg), propofol (2mg/kg) and cisatracurium (0.15 mg/kg). A double-lumen endobronchial tube is placed to perform differential one-lung ventilation. The left radial arteria is secured for arterial pressure monitoring and arterial blood sampling. Monitoring included electrocardiography, haemoglobin oxygen saturation, end-tidal carbon dioxide tension and invasive arterial pressure. A bolus of ketamine or placebo, intravenous or epidurally, according to the group of study is administered before skin incision. The study drug is prepared and placed by a nurse who does not participate in the anesthesia or evaluation of postoperative pain. Anesthesia is maintained by sevoflurane 1.5-2%, fentanyl and cisatracurium titrated according to the patients´needs. At the end of the skin closure, 5-7 ml of ropivacaine 0.2% is administered epidurally followed by epidural infusion of ropivacaine 0.15% and fentanyl 2mcg/ml and epidural or intravenous infusion of ketamine or placebo according to the group. Patients are extubated in the operating room and transferred to the postanesthesia care unit.

Epidural infusion is maintained for 48 hours at a rate of 3-6ml/h, boluses of 2-3 ml are allowed every 20 minutes.The protocol for rescue analgesia consisted of the first administration of iv metamizol 2g per 8 hours. The second rescue analgesia line consisted of the adjunction of subcutaneous methadone 3-6 mg per 8 hours. Patients remained in the postanesthesia care unit for 24 hours. Pain at rest and on coughing is assessed with VAS at 1-4-8-12-24-72 hours. Side effects including cognitive effects such as nightmares or hallucinations, blurred vision, sedation (not arousable except by persisting verbal or tactile stimulation), or haemodynamic effects (hypertension over 20% their basal values). Subjective test and QST are performed at 72h, 7 day, 3 and 6 months after surgery.

The investigators considered 30 patients per group in order to obtain 3 points of difference of the ratio between the hyperalgesia area and the incision length, considering a SD of differences of 3.5, type I error of 0.05 and statistical power of 0.9.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE
  • Persistent Pain
  • Postoperative Hyperalgesia
Intervention  ICMJE Drug: Ketamine
Intravenous ketamine 0.5mg/kg(induction of anesthesia)and 0.25 mg/kg/h for 48h Epidural Ketamine 0.5 mg/kg(induction of anesthesia)and 0.25 mg/kg/h for 48h
Study Arms  ICMJE
  • Active Comparator: Epidural ketamine
    • Bolus of epidural ketamine during the induction of anesthesia
    • Epidural infusion of ketamine during the first 48 h after surgery

    Postoperative analgesia: Epidural "Patient Controlled Analgesia" with ropivacaine and fentanyl

    Intervention: Drug: Ketamine
  • Active Comparator: Intravenous ketamine
    • Bolus of intravenous ketamine administered during the induction of anesthesia
    • Intravenous infusion during the first 48 hours after surgery

    Postoperative analgesia: Epidural "Patient Controlled Analgesia" with ropivacaine plus fentanyl

    Intervention: Drug: Ketamine
  • Placebo Comparator: Placebo
    Postoperative analgesia: Epidural "Patient Controlled Analgesia" with ropivacaine and fentanyl
    Intervention: Drug: Ketamine
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 20, 2015)
104
Original Estimated Enrollment  ICMJE
 (submitted: November 18, 2010)
90
Actual Study Completion Date  ICMJE December 2011
Actual Primary Completion Date October 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients over 18 years old submitted to thoracotomy or minithoracotomy expected to be extubated in the operating room

Exclusion Criteria:

  • Allergy or intolerance to ketamine, local anesthetics or opioids
  • Chronic preoperative pain
  • Chronic opioid treatment
  • Drug addiction
  • Polyneuropathy
  • Ischemic cardiopathy
  • Psychiatric disease
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01243801
Other Study ID Numbers  ICMJE BTB-10
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Beatriz Tena, Hospital Clinic of Barcelona
Original Responsible Party Beatriz Tena, Anesthesiology Department. Hospital Clinic Barcelona
Current Study Sponsor  ICMJE Hospital Clinic of Barcelona
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Beatriz Tena, MD Hospital Clinic of Barcelona
Study Director: Carmen Gomar, PhD Hospital Clinic of Barcelona
Study Chair: Irene Rovira, PhD Hospital Clinic of Barcelona
Study Chair: Maria J Jimenez, PhD Hospital Clinic of Barcelona
Study Chair: Guillermina Fita, PhD Hospital Clinic of Barcelona
Study Chair: Samuel Garcia, MD Hospital Clinic of Barcelona
Study Chair: Jordi Perez, PhD Hospital Clinic of Barcelona
Study Chair: Daniel Poggio, MD Hospital Clinic of Barcelona
Study Chair: Jose Rios Hospital Clinic of Barcelona
PRS Account Hospital Clinic of Barcelona
Verification Date March 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP