NCT01301079

Brief Summary

The aim of this study was to determine if the addition of ketamine reduces remifentanil-induced hyperalgesia, improves its analgesic effect, inhibits IL(interleukin)-6 and IL-8 (inflammatory cytokines), and stimulates IL-10 (an anti-inflammatory cytokine).

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
60

participants targeted

Target at below P25 for phase_3 pain

Timeline
Completed

Started Sep 2010

Typical duration for phase_3 pain

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

September 1, 2010

Completed
6 months until next milestone

First Submitted

Initial submission to the registry

February 22, 2011

Completed
1 day until next milestone

First Posted

Study publicly available on registry

February 23, 2011

Completed
1.5 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

September 1, 2012

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

September 1, 2012

Completed
2.2 years until next milestone

Results Posted

Study results publicly available

November 10, 2014

Completed
Last Updated

November 10, 2014

Status Verified

October 1, 2014

Enrollment Period

2 years

First QC Date

February 22, 2011

Results QC Date

November 10, 2013

Last Update Submit

November 6, 2014

Conditions

PainHyperalgesiaInflammatory Response

Keywords

RemifentanilHyperalgesiaKetamineVon Frey's filamentAlgometerInterleukinesOpioid-induced hyperalgesia

Outcome Measures

Primary Outcomes (12)

  • Pain 30 Minutes

    The scale measure pain after 30 minutes (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.

    30 minutes

  • Pain 60 Minutes

    The scale measure pain after 60 minutes (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.

    60 minutes

  • Pain 90 Minutes

    The scale measure pain after 90 minutes (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.

    90 minutes

  • Pain 120 Minutes

    The scale measure pain after 120 minutes (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.

    120 minutes

  • Pain 150 Minutes

    The scale measure pain after 150 minutes (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.

    150 minutes

  • Pain 180 Minutes

    The scale measure pain after 180 minutes (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.

    180 minutes

  • Pain 210 Minutes

    The scale measure pain after 210 minutes (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.

    210 minutes

  • Pain 240 Minutes

    The scale measure pain after 240 minutes (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.

    240 minutes

  • Pain 6 Hours

    The scale measure pain after 6 hours (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.

    6 hours

  • Pain 12 Hours

    The scale measure pain after 12 hours (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.

    12 hours

  • Pain 18 Hours

    The scale measure pain after 18 hours (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.

    18 hours

  • Pain 24 Hours

    The scale measure pain after 24 hours (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.

    24 hours

Secondary Outcomes (24)

  • Time to First Morphine Supplementation

    24 hours

  • Morphine Consumption Within 24 h

    24 hours

  • Hyperalgesia in the Preoperative Period as Measured With Monofilaments in Thenar Eminence

    Before the procedure (Baseline)

  • Hyperalgesia in the Postoperative Period as Measured With Monofilaments in Thenar Eminence

    24 hours after procedure

  • Hyperalgesia in the Preoperative Period as Measured With Monofilaments in the Periumbilical Region

    Before the procedure (Baseline)

  • +19 more secondary outcomes

Study Arms (2)

Ketamine

ACTIVE COMPARATOR

A cardioscope, a capnograph, a pulse oximeter, and a noninvasive blood pressure meter were used to monitor the patients. Propofol (2-4 mg/kg), remifentanil (1 μg/kg), and atracurium (0.5 mg/kg) were administered for intubation. Atracurium was titrated to maintain muscle relaxation. Anesthesia was maintained with remifentanil, 0.8% isoflurane, and 50% oxygen without nitrous oxide. Infusion of the solutions was continued until skin closure. The patients in group ketamine received remifentanil (0.4 μg/kg/min) and ketamine (5 μg/kg/min). Remifentanil was administered as necessary until skin closure. Neostigmine was used for antagonizing the neuromuscular block.

Drug: Ketamine

Saline

PLACEBO COMPARATOR

A cardioscope, a capnograph, a pulse oximeter, and a noninvasive blood pressure meter were used to monitor the patients. Propofol (2-4 mg/kg), 1 μg/kg remifentanil, and atracurium (0.5 mg/kg) were administered for intubation. Atracurium was titrated to maintain muscle relaxation. Anesthesia was maintained with remifentanil, 0.8% isoflurane, and 50% oxygen without nitrous oxide. Infusion of the solutions was continued until skin closure. The patients in group saline received remifentanil (0.4 μg/kg/min) and saline solution. Remifentanil was administered as necessary until skin closure. Neostigmine was used for antagonizing the neuromuscular block.

Drug: Saline

Interventions

KetamineDRUG

Patients in group ketamine was administrated ketamine (5mcg/kg/min) during the surgery.

Ketamine
SalineDRUG

Patients in group N (placebo) was administrated saline during surgery.

Saline

Eligibility Criteria

Age18 Years - 78 Years
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • ≥ 18 years old
  • both sexes
  • ASA physical status I or II
  • undergoing laparoscopic cholecystectomy

You may not qualify if:

  • chronic users of analgesics or had used opioids within 12 h of surgery
  • history of drug or alcohol abuse or psychiatric disorder
  • contraindications to self-administration of opioids (ie, unable to understand the patient-controlled analgesia \[PCA\] device)
  • contraindication for the use of ketamine, such as a psychiatric disorder, acute cardiovascular disorder, or unstable hypertension

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Federal University of São Paulo

São Paulo, São Paulo, Brazil

Location

Related Publications (10)

  • Liang D, Shi X, Qiao Y, Angst MS, Yeomans DC, Clark JD. Chronic morphine administration enhances nociceptive sensitivity and local cytokine production after incision. Mol Pain. 2008 Feb 22;4:7. doi: 10.1186/1744-8069-4-7.

    PMID: 18294378BACKGROUND

  • Zhang RX, Li A, Liu B, Wang L, Ren K, Zhang H, Berman BM, Lao L. IL-1ra alleviates inflammatory hyperalgesia through preventing phosphorylation of NMDA receptor NR-1 subunit in rats. Pain. 2008 Apr;135(3):232-239. doi: 10.1016/j.pain.2007.05.023. Epub 2007 Aug 6.

    PMID: 17689191BACKGROUND

  • Dale O, Somogyi AA, Li Y, Sullivan T, Shavit Y. Does intraoperative ketamine attenuate inflammatory reactivity following surgery? A systematic review and meta-analysis. Anesth Analg. 2012 Oct;115(4):934-43. doi: 10.1213/ANE.0b013e3182662e30. Epub 2012 Jul 23.

    PMID: 22826531BACKGROUND

  • Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology. 2006 Mar;104(3):570-87. doi: 10.1097/00000542-200603000-00025.

    PMID: 16508405RESULT

  • Koppert W, Sittl R, Scheuber K, Alsheimer M, Schmelz M, Schuttler J. Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans. Anesthesiology. 2003 Jul;99(1):152-9. doi: 10.1097/00000542-200307000-00025.

    PMID: 12826855RESULT

  • Guignard B, Bossard AE, Coste C, Sessler DI, Lebrault C, Alfonsi P, Fletcher D, Chauvin M. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology. 2000 Aug;93(2):409-17. doi: 10.1097/00000542-200008000-00019.

    PMID: 10910490RESULT

  • Celerier E, Rivat C, Jun Y, Laulin JP, Larcher A, Reynier P, Simonnet G. Long-lasting hyperalgesia induced by fentanyl in rats: preventive effect of ketamine. Anesthesiology. 2000 Feb;92(2):465-72. doi: 10.1097/00000542-200002000-00029.

    PMID: 10691234RESULT

  • Joly V, Richebe P, Guignard B, Fletcher D, Maurette P, Sessler DI, Chauvin M. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology. 2005 Jul;103(1):147-55. doi: 10.1097/00000542-200507000-00022.

    PMID: 15983467RESULT

  • Engelhardt T, Zaarour C, Naser B, Pehora C, de Ruiter J, Howard A, Crawford MW. Intraoperative low-dose ketamine does not prevent a remifentanil-induced increase in morphine requirement after pediatric scoliosis surgery. Anesth Analg. 2008 Oct;107(4):1170-5. doi: 10.1213/ane.0b013e318183919e.

    PMID: 18806023RESULT

  • Johnston IN, Milligan ED, Wieseler-Frank J, Frank MG, Zapata V, Campisi J, Langer S, Martin D, Green P, Fleshner M, Leinwand L, Maier SF, Watkins LR. A role for proinflammatory cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine. J Neurosci. 2004 Aug 18;24(33):7353-65. doi: 10.1523/JNEUROSCI.1850-04.2004.

    PMID: 15317861RESULT

MeSH Terms

Conditions

PainHyperalgesia

Interventions

KetamineSodium Chloride

Condition Hierarchy (Ancestors)

Neurologic ManifestationsSigns and SymptomsPathological Conditions, Signs and SymptomsSomatosensory DisordersSensation DisordersNervous System Diseases

Intervention Hierarchy (Ancestors)

CyclohexanesCycloparaffinsHydrocarbons, AlicyclicHydrocarbons, CyclicHydrocarbonsOrganic ChemicalsChloridesHydrochloric AcidChlorine CompoundsInorganic ChemicalsSodium Compounds

Results Point of Contact

Title
Plínio da Cunha Leal
Organization
Federal University of Sao Paulo
pliniocunhaleal@hotmail.com
55-98-8852-2021

Study Officials

  • Plínio da Cunha Leal, PhD

    Federal University of São Paulo

    PRINCIPAL INVESTIGATOR

Publication Agreements

PI is Sponsor Employee
No
Restrictive Agreement
No

Study Design

Study Type
interventional
Phase
phase 3
Allocation
RANDOMIZED
Masking
QUADRUPLE
Who Masked
PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
Purpose
PREVENTION
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
Master's degree

Study Record Dates

First Submitted

February 22, 2011

First Posted

February 23, 2011

Study Start

September 1, 2010

Primary Completion

September 1, 2012

Study Completion

September 1, 2012

Last Updated

November 10, 2014

Results First Posted

November 10, 2014

Record last verified: 2014-10

Locations

BR(1)