Persistent Pain Clinical Trial
Official title:
Phase 4 Study of Prevention of Persistent Postsurgical Pain After Thoracotomy Using Ketamine
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.
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.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention
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