PainPhase 3NCT01301079

Evaluation of the Effect of Ketamine on Remifentanil-induced Hyperalgesia

A Phase 3 study testing Ketamine and Saline in people with Pain and Hyperalgesia, run by Federal University of São Paulo at 1 site in Brazil.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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). Read more about this study

Who is it for?: Ages 18 to 78 years
Conditions the study is for: Pain, Hyperalgesia, Inflammatory Response
What is being tested?: Ketamine and Saline
Type of treatment: Injection or infusion
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 60 participants
Where: 1 siteBrazil
Study dates: Sep 2010to Sep 2012
Phase: Phase 3
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 78 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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

Who cannot join

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

Trial locations and contacts

1 site in 1 country.

Brazil1 site

Federal University of São Paulo
São Paulo, São Paulo

Other trials in Brazil

About this study

Official title: Evaluation of the Effect of Ketamine on Remifentanil-induced Hyperalgesia Using Filaments, an Algometer, and Interleukins: a Double-blind, Randomized Study

Read the detailed description

Opioids are very effective in pain relief, but they might lower pain threshold, making the patient more sensitive to a pain stimulus, a condition known as hyperalgesia [Angst; Clarck, 2006]. Opioid-induced hyperalgesia (OIH) is usually defined as a reduction in nociceptive thresholds in the peripheral field of the sensitized fibers [Koppert et al., 2003], and it is associated with increased pain and higher demand for postoperative analgesia [Guignard et al., 2000]. This phenomenon adversely impacts pain control, and has been suggested to occur in the peri-operative context, especially associated with the use of remifentanil, a short-acting opioid [Guignard et al., 2000].

Several mechanisms have been proposed to explain the hyperalgesia phenomenon, but the most important seems to be the activation of N-methyl-D-aspartate (NMDA) receptors [Célèrier et al., 2000]. Ketamine is a NMDA receptor antagonist that has been shown to reduce postoperative pain and the need for postoperative anesthetics and analgesics. Therefore, it is proposed that ketamine could prevent hyperalgesia, resulting in more effective and long-lasting postsurgical analgesia [Célèrier et al. 2000].

The results of studies of low dose of ketamine in the prevention of remifentanil-induced hyperalgesia are controversial. Joly et al. [2005] demonstrated a reduction in the consumption of opioids and in hyperalgesia assessed with monofilaments. However, Engelhardt et al [2008] showed no differences in pain scores or in postoperative opioid consumption.

In addition, some authors observed higher levels of proinflammatory cytokines, associated with increased pain in mice receiving chronic opioid (morphine) infusion [Johnston et al., 2004; Liang et al., 2008]. Also, administration of proinflammatory cytokine inhibitors reduced phosphorylation of NMDA receptors [Zhang et al., 2008]. However, no study has examined the relationship between the use of remifentanil, the most frequently implicated opioid in OIH [Guignard et al., 2000], ketamine (drug capable of inhibiting NMDA-receptors and cytokines) [Dale et al., 2012], and the inflammatory response.

The aim of this study was to determine if the addition of ketamine reduces remifentanil-induced hyperalgesia, improves its analgesic effect, inhibits IL-6 and IL-8 (inflammatory cytokines), and stimulates IL-10 (an anti-inflammatory cytokine) in patients submitted to laparoscopic cholecystectomy, a procedure with an usually neglected potential for postoperative pain and that has been poorly investigated in association with OIH.

Conditions: Pain, Hyperalgesia, Inflammatory Response
Being tested: Ketamine, Saline
Keywords: Remifentanil, Hyperalgesia, Ketamine, Von Frey's filament, Algometer, Interleukines, Opioid-induced hyperalgesia
Medical subject headings: Pain, Hyperalgesia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

KetamineDrug
Patients in group ketamine was administrated ketamine (5mcg/kg/min) during the surgery.
SalineDrug
Patients in group N (placebo) was administrated saline during surgery.

Study groups in NCT01301079
Study group	Role	What they receive
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. Receives: 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. Receives: Drug: Saline

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 24 hours

Secondary outcomes (24)

Time to First Morphine Supplementation
Measured: 24 hours
Morphine Consumption Within 24 h
Measured: 24 hours
Hyperalgesia in the Preoperative Period as Measured With Monofilaments in Thenar Eminence
The pain threshold was assessed using six von Frey monofilaments (0,05 g; 0,2 g; 2 g; 4 g; 10 g e 300 g) in thenar eminence in the preoperative period. The use of different von Frey monofilaments, starting with the lightest and ending with the heaviest, was separated by at least 30 seconds to reduce any anticipated responses due to a new stimulation that was performed too soon after the preceding stimulation. Three assessments were made for each monofilament, and this was considered positive when the patient responded to two of the determinations for each monofilament.
Measured: Before the procedure (Baseline)
Hyperalgesia in the Postoperative Period as Measured With Monofilaments in Thenar Eminence
The pain threshold was assessed using six von Frey monofilaments (0,05 g; 0,2 g; 2 g; 4 g; 10 g e 300 g) in thenar eminence in the postoperative period (24 hours after procedure). The use of different von Frey monofilaments, starting with the lightest and ending with the heaviest, was separated by at least 30 seconds to reduce any anticipated responses due to a new stimulation that was performed too soon after the preceding stimulation. Three assessments were made for each monofilament, and this was considered positive when the patient responded to two of the determinations for each monofilament.
Measured: 24 hours after procedure
Hyperalgesia in the Preoperative Period as Measured With Monofilaments in the Periumbilical Region
The pain threshold was assessed using six von Frey monofilaments (0,05 g; 0,2 g; 2 g; 4 g; 10 g e 300 g) in the periumbilical region in the preoperative period. The use of different von Frey monofilaments, starting with the lightest and ending with the heaviest, was separated by at least 30 seconds to reduce any anticipated responses due to a new stimulation that was performed too soon after the preceding stimulation. Three assessments were made for each monofilament, and this was considered positive when the patient responded to two of the determinations for each monofilament.
Measured: Before the procedure (Baseline)
Hyperalgesia in the Postoperative Period as Measured With Monofilaments in the Periumbilical Region
The pain threshold was assessed using six von Frey monofilaments (0,05 g; 0,2 g; 2 g; 4 g; 10 g e 300 g) in the periumbilical region in the postoperative period (24h after the procedure). The use of different von Frey monofilaments, starting with the lightest and ending with the heaviest, was separated by at least 30 seconds to reduce any anticipated responses due to a new stimulation that was performed too soon after the preceding stimulation. Three assessments were made for each monofilament, and this was considered positive when the patient responded to two of the determinations for each monofilament.
Measured: 24h after the procedure
Hyperalgesia in the Preoperative Period as Measured With Algometer in Thenar Eminence
The mechanical pain threshold was evaluated using an algometer. The pressure was increased by 0.1 kgf/second until the patient complained of pain. The mean of three determinations was calculated.
Measured: Baseline (before the procedure)
Hyperalgesia in the Postoperative Period as Measured With Algometer in Thenar Eminence
The mechanical pain threshold was evaluated using an algometer. The pressure was increased by 0.1 kgf/second until the patient complained of pain. The mean of three determinations was calculated.
Measured: 24 h after the procedure
Hyperalgesia in the Preoperative Period as Measured With Algometer in the Periumbilical Region
The mechanical pain threshold was evaluated using an algometer. The pressure was increased by 0.1 kgf/second until the patient complained of pain. The mean of three determinations was calculated.
Measured: Baseline (before the surgery)
Hyperalgesia in the Postoperative Period as Measured With Algometer in the Periumbilical Region
The mechanical pain threshold was evaluated using an algometer. The pressure was increased by 0.1 kgf/second until the patient complained of pain. The mean of three determinations was calculated.
Measured: 24 h after the procedure
Extension of Hyperalgesia
The 300-g filament was used 24 hours after the operation to induce a stimulus and delineate the extent of hyperalgesia from the periumbilical region. The stimulus was started outside the periumbilical region, where no pain sensation was reported, and continued every 0.5 cm until the 4 points of the periumbilical scar were reached (top, right side, left side, and bottom). The first point where the patient complained of pain was marked. If no pain sensation was reported, the stimulus was terminated 0.5 cm from the incision. The distance of each point from the surgical incision was measured, and the sum of the distances of the points was determined.
Measured: 24 hours after the procedure
Allodynia as Detected With a Soft Brush in the Periumbilical Region Before the Procedure
The evaluations using the soft brush were performed 2-3 cm from the incision in the periumbilical region (where the large trocar was placed) before the procedure
Measured: Before the procedure (Baseline)
Allodynia as Detected With a Soft Brush in the Periumbilical Region 24 h After the Procedure
The evaluations using the soft brush were performed 2-3 cm from the incision in the periumbilical region (where the large trocar was placed) 24 h after the procedure
Measured: 24 h after the procedure
Allodynia as Detected With a Soft Brush in the Thenar Eminence Before the Procedure
The evaluations using the soft brush were performed in the thenar eminence of the nondominant hand before the procedure
Measured: Before the procedure (Baseline)
Allodynia as Detected With a Soft Brush in the Thenar Eminence 24 h After the Procedure
The evaluations using the soft brush were performed in the thenar eminence of the non dominant hand 24 h after the procedure
Measured: 24 h after the procedure
Serum Level of Interleukin (IL)-6 Before the Procedure
Blood samples were drawn in ethylenediaminetetraacetic acid (EDTA) tubes before the surgery. The blood was centrifuged to separate the plasma and was stored at -70°C. IL-6 was analyzed using the enzyme-linked immunosorbent assay (ELISA) methodology.
Measured: Baseline (Before the procedure)
Serum Level of Interleukin (IL)-6 5 h After the Procedure
Blood samples were drawn in ethylenediaminetetraacetic acid (EDTA) tubes 5 h after the surgery. The blood was centrifuged to separate the plasma and was stored at -70°C. IL-6 was analyzed using the enzyme-linked immunosorbent assay (ELISA) methodology.
Measured: 5 h after the procedure
Serum Level of Interleukin (IL)-6 24 h After the Procedure
Blood samples were drawn in ethylenediaminetetraacetic acid (EDTA) tubes 24 h after the surgery. The blood was centrifuged to separate the plasma and was stored at -70°C. IL-6 was analyzed using the enzyme-linked immunosorbent assay (ELISA) methodology.
Measured: 24 h after the procedure
Serum Level of Interleukin (IL)-8 Before the Procedure
Blood samples were drawn in ethylenediaminetetraacetic acid (EDTA) tubes before the surgery. The blood was centrifuged to separate the plasma and was stored at -70°C. IL-8 was analyzed using the enzyme-linked immunosorbent assay (ELISA) methodology.
Measured: Baseline (Before the procedure)
Serum Level of Interleukin (IL)-8 5 h After the Procedure
Blood samples were drawn in ethylenediaminetetraacetic acid (EDTA) tubes 5 h after the surgery. The blood was centrifuged to separate the plasma and was stored at -70°C. IL-8 was analyzed using the enzyme-linked immunosorbent assay (ELISA) methodology.
Measured: 5 h after the procedure
Serum Level of Interleukin (IL)-8 24 h After the Procedure
Blood samples were drawn in ethylenediaminetetraacetic acid (EDTA) tubes 24 h after the surgery. The blood was centrifuged to separate the plasma and was stored at -70°C. IL-8 was analyzed using the enzyme-linked immunosorbent assay (ELISA) methodology.
Measured: 24 h after the procedure
Serum Level of Interleukin (IL)-10 Before the Procedure
Blood samples were drawn in ethylenediaminetetraacetic acid (EDTA) tubes before the surgery. The blood was centrifuged to separate the plasma and was stored at -70°C. IL-6 was analyzed using the enzyme-linked immunosorbent assay (ELISA) methodology.
Measured: Baseline (Before the procedure)
Serum Level of Interleukin (IL)-10 5h After the Procedure
Blood samples were drawn in ethylenediaminetetraacetic acid (EDTA) tubes 5 h after the surgery. The blood was centrifuged to separate the plasma and was stored at -70°C. IL-10 was analyzed using the enzyme-linked immunosorbent assay (ELISA) methodology.
Measured: 5h after the procedure
Serum Level of Interleukin (IL)-10 24 h After the Procedure
Blood samples were drawn in ethylenediaminetetraacetic acid (EDTA) tubes 24 h after the surgery. The blood was centrifuged to separate the plasma and was stored at -70°C. IL-6 was analyzed using the enzyme-linked immunosorbent assay (ELISA) methodology.
Measured: 24 h after the procedure

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Sep 2010Sep 2012

First posted23 Feb 2011 (estimated)
Study startSep 2010
Primary completionSep 2012
Study completionSep 2012

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (10)Papers the sponsor has linked to this study.
Other trials for PainStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 3
Primary purpose: Prevention
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 60 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01301079
Sponsor's protocol ID: anaana
Status last verified: Oct 2014
First submitted: 22 Feb 2011
Last updated: 10 Nov 2014
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

Publications

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.
PubMed 18294378
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.
PubMed 17689191
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.
PubMed 22826531
Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology. 2006 Mar;104(3):570-87. doi: 10.1097/00000542-200603000-00025.
PubMed 16508405
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.
PubMed 12826855
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.
PubMed 10910490
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.
PubMed 10691234
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.
PubMed 15983467
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.
PubMed 18806023
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.
PubMed 15317861

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 10 Nov 2014. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Evaluation of the Effect of Ketamine on Remifentanil-induced Hyperalgesia Using Filaments, an Algometer, and Interleukins: a Double-blind, Randomized Study
ClinicalTrials.gov ID: NCT01301079
Acronym / sponsor ID: anaana
Conditions: Pain, Hyperalgesia, Inflammatory Response
Keywords: Remifentanil, Hyperalgesia, Ketamine, Von Frey's filament, Algometer, Interleukines, Opioid-induced hyperalgesia
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 60 participants (actual)
Lead sponsor: Federal University of São PauloUniversity, hospital or other
Collaborators: Fundação de Amparo à Pesquisa do Estado de São Paulo
Study start: Sep 2010
Primary completion: Sep 2012 (actual)
Study completion: Sep 2012 (actual)
First posted: 23 Feb 2011 (estimated)
Results: Posted 10 Nov 2014

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Prevention
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 2

Arm	Type	Receives
Ketamine	Active comparator	Drug: KetamineA 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.
Saline	Placebo comparator	Drug: SalineA 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.

Who may qualify

Ages: 18 to 78 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (4 listed)

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

Key exclusion criteria (4 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
KetaminePatients in group ketamine was administrated ketamine (5mcg/kg/min) during the surgery.	Drug	Ketamine
SalinePatients in group N (placebo) was administrated saline during surgery.	Drug	Saline

Primary outcome

Pain 30 Minutes
Time frame: 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.
Pain 60 Minutes
Time frame: 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.
Pain 90 Minutes
Time frame: 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.
Pain 120 Minutes
Time frame: 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.
Pain 150 Minutes
Time frame: 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.
Pain 180 Minutes
Time frame: 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.
Pain 210 Minutes
Time frame: 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.
Pain 240 Minutes
Time frame: 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.
Pain 6 Hours
Time frame: 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.
Pain 12 Hours
Time frame: 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.
Pain 18 Hours
Time frame: 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.
Pain 24 Hours
Time frame: 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 secondary outcomes

Time to First Morphine Supplementation
Time frame: 24 hours
Morphine Consumption Within 24 h
Time frame: 24 hours
Hyperalgesia in the Preoperative Period as Measured With Monofilaments in Thenar Eminence
Time frame: Before the procedure (Baseline)
Hyperalgesia in the Postoperative Period as Measured With Monofilaments in Thenar Eminence
Time frame: 24 hours after procedure
Hyperalgesia in the Preoperative Period as Measured With Monofilaments in the Periumbilical Region
Time frame: Before the procedure (Baseline)
Hyperalgesia in the Postoperative Period as Measured With Monofilaments in the Periumbilical Region
Time frame: 24h after the procedure
Hyperalgesia in the Preoperative Period as Measured With Algometer in Thenar Eminence
Time frame: Baseline (before the procedure)
Hyperalgesia in the Postoperative Period as Measured With Algometer in Thenar Eminence
Time frame: 24 h after the procedure
Hyperalgesia in the Preoperative Period as Measured With Algometer in the Periumbilical Region
Time frame: Baseline (before the surgery)
Hyperalgesia in the Postoperative Period as Measured With Algometer in the Periumbilical Region
Time frame: 24 h after the procedure
Extension of Hyperalgesia
Time frame: 24 hours after the procedure
Allodynia as Detected With a Soft Brush in the Periumbilical Region Before the Procedure
Time frame: Before the procedure (Baseline)
Allodynia as Detected With a Soft Brush in the Periumbilical Region 24 h After the Procedure
Time frame: 24 h after the procedure
Allodynia as Detected With a Soft Brush in the Thenar Eminence Before the Procedure
Time frame: Before the procedure (Baseline)
Allodynia as Detected With a Soft Brush in the Thenar Eminence 24 h After the Procedure
Time frame: 24 h after the procedure
Serum Level of Interleukin (IL)-6 Before the Procedure
Time frame: Baseline (Before the procedure)
Serum Level of Interleukin (IL)-6 5 h After the Procedure
Time frame: 5 h after the procedure
Serum Level of Interleukin (IL)-6 24 h After the Procedure
Time frame: 24 h after the procedure
Serum Level of Interleukin (IL)-8 Before the Procedure
Time frame: Baseline (Before the procedure)
Serum Level of Interleukin (IL)-8 5 h After the Procedure
Time frame: 5 h after the procedure
Serum Level of Interleukin (IL)-8 24 h After the Procedure
Time frame: 24 h after the procedure
Serum Level of Interleukin (IL)-10 Before the Procedure
Time frame: Baseline (Before the procedure)
Serum Level of Interleukin (IL)-10 5h After the Procedure
Time frame: 5h after the procedure
Serum Level of Interleukin (IL)-10 24 h After the Procedure
Time frame: 24 h after the procedure

Results and safety

Results posted to the registry on 10 Nov 2014, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Ketamine	30	28
Saline	30	28

Primary outcome: Pain 30 Minutes

Time frame: 30 minutes. Mean (Standard Deviation). Unit: units on a scale

Measure	Ketamine n = 28	Saline n = 28
Value	5.5 (3.5)	6.2 (2.6)

Ketamine vs Saline: p = 0.386, t-test, 2 sided

Primary outcome: Pain 60 Minutes

Time frame: 60 minutes. Mean (Standard Deviation). Unit: units on a scale

Measure	Ketamine n = 28	Saline n = 28
Value	4.6 (3.0)	5.1 (2.5)

Ketamine vs Saline: p = 0.499, t-test, 1 sided

Primary outcome: Pain 90 Minutes

Time frame: 90 minutes. Mean (Standard Deviation). Unit: units on a scale

Measure	Ketamine n = 28	Saline n = 28
Value	3.4 (2.4)	3.4 (2.3)

Ketamine vs Saline: p = 0.909, t-test, 2 sided

Primary outcome: Pain 120 Minutes

Time frame: 120 minutes. Mean (Standard Deviation). Unit: units on a scale

Measure	Ketamine n = 28	Saline n = 28
Value	2.2 (2.1)	2.0 (1.8)

Ketamine vs Saline: p = 0.737, t-test, 2 sided

24 secondary outcomes are reported in the full results.

Adverse events

Time frame: 24 hours. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Ketamine	0 of 28 (0%)	16 of 28 (57.1%)	Not reported
Saline	0 of 28 (0%)	8 of 28 (28.6%)	Not reported

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 10 Nov 2014.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 18294378Liang 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.
Background: PubMed 17689191Zhang 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.
Background: PubMed 22826531Dale 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.
Results publication: PubMed 16508405Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology. 2006 Mar;104(3):570-87. doi: 10.1097/00000542-200603000-00025.
Results publication: PubMed 12826855Koppert 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.
Results publication: PubMed 10910490Guignard 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.
Results publication: PubMed 10691234Celerier 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.
Results publication: PubMed 15983467Joly 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.
Results publication: PubMed 18806023Engelhardt 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.
Results publication: PubMed 15317861Johnston 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.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Plínio da Cunha Leal, PhD principal investigator

Federal University of São Paulo

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Ketamine and Saline in people with Pain and Hyperalgesia, run by Federal University of São Paulo at 1 site in Brazil.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 Nov 2014. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Brazil. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 10 Nov 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Pain 30 Minutes (time frame: 30 minutes). The study lists 12 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01301079, which also lists 10 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Nov 2014.