CompletedNCT01594047Updated Oct 1, 2025Results posted

Perioperative Opioid-induced Hyperalgesia and Its Prevention With Ketamine and Methadone

An interventional study of ketamine infusion and Methadone PCA in Post Operative Pain and Hyperalgesia, sponsored by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano. Completed at 1 site in Italy. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2025-10-01.

Sponsored by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano · Not applicable, Interventional, and Treatment

From the registry’s dates

Registered 2 years 5 months after the study started (first participant enrolled Dec 2009, registered May 2012).

Phase: Not applicable
Study type: Interventional
Enrollment: 113
Allocation: Randomized
Ages: 18 Years to 75 Years
Sex: All

Study summary

Background: In perioperative period inhibition of N-Methyl-D-Aspartate receptor prevents opioid-induced hyperalgesia and reduce postoperative opioid requirement after abdominal surgery. Methadone is both a µ-opioid receptor agonist like Morphine and a N-Methyl-D-Aspartate antagonist. Study Aim. To evaluate the efficacy of intraoperative Ketamine and postoperative Methadone analgesia in preventing opioid-induced hyperalgesia after abdominal surgery.

Read the detailed description

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Conditions studied

Post Operative Pain
Hyperalgesia

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Keywords

hyperalgesia
Patient controlled analgesia
morphine
methadone
ketamine

In context

Pain, Postoperative

5,640 studies on the registry are indexed under Pain, Postoperative; 1,230 are open to participants now.

This study's enrollment of 113 is above the median of 75 across 4,821 interventional studies indexed under Pain, Postoperative.

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Lead sponsor

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano is the lead sponsor of 172 studies on the registry; 50 are open to participants now.

Browse Fondazione IRCCS Istituto Nazionale dei Tumori, Milano studies →

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 75 Years
Sexes eligible: All
Accepts healthy volunteers: No

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

Inclusion criteria

patients undergoing open colo-rectal surgery

Exclusion criteria

Exclusion Criteria:

ASA status more than II, history of chronic pain, ischemic heart disease or chronic pulmonary disease, allergy to any drugs used in the protocol. Body Max Index more than 35.

Study design

Phase: Not applicable
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Double (Participant, Investigator)
Enrollment: 113 participants (actual)

Study arms

No intervention
zero/morphine
Patient received a standard balance anaesthesia and morphine for post operative pain.
Experimental
ketamine/morphine
Ketamine infusion scheme: 5mcg/Kg/min from induction od anaesthesia for 10 min, than 2,5mcg/Kg/min for 20 min and than 2 mcg/Kg/min to the end of surgery.
Drug: ketamine infusion
Experimental
zero/metadone
Methadone PCA
Drug: Methadone PCA
Experimental
ketamine/methadone
Ketamine infusion scheme: 5mcg/Kg/min from induction od anaesthesia for 10 min, than 2,5mcg/Kg/min for 20 min and than 2 mcg/Kg/min to the end of surgery. Methadone administered by a PCA system (dose 2 mg, lock-out 12min.).
Drug: ketamine infusion · Drug: Methadone PCA

Interventions

Drugketamine infusion
Ketamine infusion scheme: 5mcg/Kg/min from induction od anaesthesia for 10 min, than 2,5mcg/Kg/min for 20 min and than 2 mcg/Kg/min to the end of surgery
Also known as: hyperalgesia-blocker
DrugMethadone PCA
Methadone administered by a PCA system (dose 2 mg, lock-out 12min.)
Also known as: hyperalgesia-blocker

What researchers measure

Primary outcomes

the Extent of Hyperalgesia Area Proximal to Surgical Wound
Hyperalgesia is determined by stimulating with a won Fray hair N°16 along three lines at a right angle to the top, middle, and bottom sides of the surgical incision. Each line starts from the edge of the abdomen to the surgical incision. Stimulation continue from the edge toward the surgical incision until the patients reported a worsening in sensation The distance from the incision to where sensation change was measured. The mean of the three assessments was used as a measure of the extent of the hyperalgesia area.
Time frame: 24 and 48 hours after surgery

Secondary outcomes

Pain Intensity Measured by a Numeric Rating Scale (NRS)
A Numerical Rating Scale (NRS) from 0 to 10 is used as a measure of pain intensity. Zero indicates the absence of any pain and 10 the worse pain never felt.
Time frame: 24 and 48 hours after surgery
Opioid Consumption
Cumulative opioid consumption at 48 hours from surgery ( end of the study)
Time frame: 48 hours

Results

Posted Oct 2, 2023

Limitations and caveats

We chose to analyse mechanical static punctuate hyperalgesia along three lines lateral to the surgical wound, as it is the most common test used to characterise the effect of ketamine and others NMDAr blockers on neuroplasticity in surgical patients. We are aware that there is increasing evidence that the quantitative sensory testing may be more effective and specific in detecting and defining hyperalgesia, both in acute and chronic settings.

Participant flow

Participant flow — Overall Study
Milestone	Zero/Morphine	Ketamine/Morphine	Zero/Metadone	Ketamine/Methadone
Started	29	30	27	27
Completed	24	25	23	24
Not completed	5	5	4	3

Outcome measures

Primarythe Extent of Hyperalgesia Area Proximal to Surgical Wound

Hyperalgesia is determined by stimulating with a won Fray hair N°16 along three lines at a right angle to the top, middle, and bottom sides of the surgical incision. Each line starts from the edge of the abdomen to the surgical incision. Stimulation continue from the edge toward the surgical incision until the patients reported a worsening in sensation The distance from the incision to where sensation change was measured. The mean of the three assessments was used as a measure of the extent of the hyperalgesia area.

Time frame:: 24 and 48 hours after surgery
Reported as:: Mean · cm

the Extent of Hyperalgesia Area Proximal to Surgical Wound
cm	Zero/Morphine	Ketamine/Morphine	Zero/Metadone	Ketamine/Methadone
24 hours	19.5 ± 12.76	14.68 ± 13.04	15.28 ± 12.72	11.04 ± 11.13
48 hours	16.04 ± 13.23	16.38 ± 14.05	18.09 ± 15.34	14.51 ± 12.75

SecondaryPain Intensity Measured by a Numeric Rating Scale (NRS)

A Numerical Rating Scale (NRS) from 0 to 10 is used as a measure of pain intensity. Zero indicates the absence of any pain and 10 the worse pain never felt.

Time frame:: 24 and 48 hours after surgery
Reported as:: Mean · units on NRS

Pain Intensity Measured by a Numeric Rating Scale (NRS)
units on NRS	Zero/Morphine	Ketamine/Morphine	Zero/Metadone	Ketamine/Methadone
NRS static 24 hours	1.92 ± 1.38	1.64 ± 1.32	0.61 ± 1.03	0.78 ± 1.28
NRS dynamic 24 hours	4.75 ± 1.80	4.68 ± 1.95	3.13 ± 2.20	3.04 ± 1.66
NRS static 48 hours	1.36 ± 1.92	0.88 ± 1.13	0.87 ± 1.36	0.5 ± 0.88
NRS dynamic 48 hours	4.27 ± 1.86	4.44 ± 1.42	2.65 ± 1.92	2.75 ± 1.96

SecondaryOpioid Consumption

Cumulative opioid consumption at 48 hours from surgery ( end of the study)

Time frame:: 48 hours
Reported as:: Mean · mg

Opioid Consumption
mg	Zero/Morphine	Ketamine/Morphine	Zero/Metadone	Ketamine/Methadone
Opioid Consumption	56.09 ± 28.99	66.9 ± 29.37	43.64 ± 20.24	38.96 ± 20.95

Adverse events

Collected over For each patient, adverse event data were collected up to 48 hours from surgery ( end of the study). Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Zero/Morphine	0/25 (0%)	0/25 (0%)	0/25 (0%)
Ketamine/Morphine	0/25 (0%)	0/25 (0%)	0/25 (0%)
Zero/Metadone	0/25 (0%)	0/25 (0%)	0/25 (0%)
Ketamine/Methadone	0/25 (0%)	0/25 (0%)	0/25 (0%)

Baseline characteristics

Age, Continuous
Age, Continuous(years)	Zero/Morphine	Ketamine/Morphine	Zero/Metadone	Ketamine/Methadone	Total
Mean	58 (40 to 75)	60 (46 to 75)	57 (42 to 70)	57 (34 to 71)	58 (34 to 75)

Sex: Female, Male
Sex: Female, Male(Participants)	Zero/Morphine	Ketamine/Morphine	Zero/Metadone	Ketamine/Methadone	Total
Female	9	6	8	10	33
Male	15	19	15	14	63

Study locations

1 site

Fondazione IRCCS Istituto Nazionale dei Tumori
Milan, 20133, Italy

References and documents

Publications

Tognoli E, Proto PL, Motta G, Galeone C, Mariani L, Valenza F. Methadone for postoperative analgesia: contribution of N-methyl-D-aspartate receptor antagonism: A randomised controlled trial. Eur J Anaesthesiol. 2020 Oct;37(10):934-943. doi: 10.1097/EJA.0000000000001217. PubMed 32516227 ↗

Timeline

Tracking since Sep 25, 2026

ElapsedEstimatedEstimated, not yet reachedSimilar studies: half by the dot; the band is the middle halfHalf of similar studies reached it by the dot; the band is the middle half, from a quarter to three quarters

Ran from Dec 2009 to primary completion in Jun 2012, 30 months.

Results were first posted in Oct 2023, 11 years 4 months after primary completion.

Of 2,089 non-industry interventional studies with no phase under Pain, Postoperative, half reached primary completion within 11 months of starting (the median), counting those still running; a quarter within 6 and three quarters within 23. This study's 30 months is above that.

Counting every sponsor, half of 2,102 studies reached it within 11 months; a quarter within 6 and three quarters within 23.

How these figures are worked out, and which studies are left out of them.

Registered: May 5, 2012
First posted: May 8, 2012
StartActual: Dec 1, 2009
Primary completionActual: Jun 1, 2012
CompletionActual: Aug 1, 2014
Results first posted: Oct 2, 2023
Last update: Oct 1, 2025

What these dates mean

Start.: When the first participant enrolled; while estimated, when the study expects to open to recruitment.
Primary completion.: When the last participant was examined or treated to collect data for the study's main question, its primary outcome. A study that stopped early gives the date its data collection stopped.
Completion.: When the last participant's last visit took place, for every outcome, secondary ones and side effects included: the end of the study. Often later than primary completion, sometimes the same day.
Actual and Est.: Actual means the registry says the date has happened. Est. (estimated) is a date the sponsor plans or expects. It can still move, and the sponsor is expected to change it to actual once it has passed.

No changes since tracking began. The registry record was last updated on Oct 1, 2025, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT01594047
Lead sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Responsible party: Emiliano Tognoli (medical doctor, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano) — Principal investigator
First posted: May 8, 2012
Start date: Dec 1, 2009
Primary completion: Jun 1, 2012
Completion: Aug 1, 2014
Results posted: Oct 2, 2023
Last update: Oct 1, 2025

Study contacts

Emiliano Tognoli

principal investigator · Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Oversight

Data monitoring committee: No

View the source record on ClinicalTrials.gov ↗

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