Post Operative Pain, Hyperalgesia
Conditions
Keywords
hyperalgesia, Patient controlled analgesia, morphine, methadone, ketamine
Brief 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.
Detailed description
not desired
Interventions
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
DRUGMethadone PCA
Methadone administered by a PCA system (dose 2 mg, lock-out 12min.)
Sponsors
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* patients undergoing open colo-rectal surgery
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| the Extent of Hyperalgesia Area Proximal to Surgical Wound | 24 and 48 hours after surgery | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pain Intensity Measured by a Numeric Rating Scale (NRS) | 24 and 48 hours after surgery | 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. |
| Opioid Consumption | 48 hours | Cumulative opioid consumption at 48 hours from surgery ( end of the study) |
Countries
Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Zero/Morphine Patient received a standard balance anaesthesia and morphine for post operative pain. | 24 |
| 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.
ketamine 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 | 25 |
| Zero/Metadone Methadone PCA
Methadone PCA: Methadone administered by a PCA system (dose 2 mg, lock-out 12min.) | 23 |
| 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.).
ketamine 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
Methadone PCA: Methadone administered by a PCA system (dose 2 mg, lock-out 12min.) | 24 |
| Total | 96 |
Baseline characteristics
| Characteristic | Zero/Morphine | Ketamine/Morphine | Zero/Metadone | Ketamine/Methadone | Total |
|---|---|---|---|---|---|
| Age, Continuous | 58 years | 60 years | 57 years | 57 years | 58 years |
| Sex: Female, Male Female | 9 Participants | 6 Participants | 8 Participants | 10 Participants | 33 Participants |
| Sex: Female, Male Male | 15 Participants | 19 Participants | 15 Participants | 14 Participants | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 25 | 0 / 25 | 0 / 25 |
| other Total, other adverse events | 0 / 25 | 0 / 25 | 0 / 25 | 0 / 25 |
| serious Total, serious adverse events | 0 / 25 | 0 / 25 | 0 / 25 | 0 / 25 |
Outcome results
Primary
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zero/Morphine | the Extent of Hyperalgesia Area Proximal to Surgical Wound | 24 hours | 19.5 cm | Standard Deviation 12.76 |
| Zero/Morphine | the Extent of Hyperalgesia Area Proximal to Surgical Wound | 48 hours | 16.04 cm | Standard Deviation 13.23 |
| Ketamine/Morphine | the Extent of Hyperalgesia Area Proximal to Surgical Wound | 48 hours | 16.38 cm | Standard Deviation 14.05 |
| Ketamine/Morphine | the Extent of Hyperalgesia Area Proximal to Surgical Wound | 24 hours | 14.68 cm | Standard Deviation 13.04 |
| Zero/Metadone | the Extent of Hyperalgesia Area Proximal to Surgical Wound | 24 hours | 15.28 cm | Standard Deviation 12.72 |
| Zero/Metadone | the Extent of Hyperalgesia Area Proximal to Surgical Wound | 48 hours | 18.09 cm | Standard Deviation 15.34 |
| Ketamine/Methadone | the Extent of Hyperalgesia Area Proximal to Surgical Wound | 24 hours | 11.04 cm | Standard Deviation 11.13 |
| Ketamine/Methadone | the Extent of Hyperalgesia Area Proximal to Surgical Wound | 48 hours | 14.51 cm | Standard Deviation 12.75 |
Secondary
Opioid Consumption
Cumulative opioid consumption at 48 hours from surgery ( end of the study)
Time frame: 48 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zero/Morphine | Opioid Consumption | 56.09 mg | Standard Deviation 28.99 |
| Ketamine/Morphine | Opioid Consumption | 66.9 mg | Standard Deviation 29.37 |
| Zero/Metadone | Opioid Consumption | 43.64 mg | Standard Deviation 20.24 |
| Ketamine/Methadone | Opioid Consumption | 38.96 mg | Standard Deviation 20.95 |
Secondary
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
Population: We performed a Dunn multiple comparison test for specific comparisons to assess group differences compared with the control group (0-Mo). Notably, the interaction term allowed us to test whether the effect of the two drugs, when jointly administered, was additive (lack of interaction) or more/ less than additive (presence of interaction). Data at 24 and 48 h were analyzed separately.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zero/Morphine | Pain Intensity Measured by a Numeric Rating Scale (NRS) | NRS dynamic 24 hours | 4.75 units on NRS | Standard Deviation 1.8 |
| Zero/Morphine | Pain Intensity Measured by a Numeric Rating Scale (NRS) | NRS static 24 hours | 1.92 units on NRS | Standard Deviation 1.38 |
| Zero/Morphine | Pain Intensity Measured by a Numeric Rating Scale (NRS) | NRS static 48 hours | 1.36 units on NRS | Standard Deviation 1.92 |
| Zero/Morphine | Pain Intensity Measured by a Numeric Rating Scale (NRS) | NRS dynamic 48 hours | 4.27 units on NRS | Standard Deviation 1.86 |
| Ketamine/Morphine | Pain Intensity Measured by a Numeric Rating Scale (NRS) | NRS static 48 hours | 0.88 units on NRS | Standard Deviation 1.13 |
| Ketamine/Morphine | Pain Intensity Measured by a Numeric Rating Scale (NRS) | NRS dynamic 48 hours | 4.44 units on NRS | Standard Deviation 1.42 |
| Ketamine/Morphine | Pain Intensity Measured by a Numeric Rating Scale (NRS) | NRS static 24 hours | 1.64 units on NRS | Standard Deviation 1.32 |
| Ketamine/Morphine | Pain Intensity Measured by a Numeric Rating Scale (NRS) | NRS dynamic 24 hours | 4.68 units on NRS | Standard Deviation 1.95 |
| Zero/Metadone | Pain Intensity Measured by a Numeric Rating Scale (NRS) | NRS dynamic 48 hours | 2.65 units on NRS | Standard Deviation 1.92 |
| Zero/Metadone | Pain Intensity Measured by a Numeric Rating Scale (NRS) | NRS static 24 hours | 0.61 units on NRS | Standard Deviation 1.03 |
| Zero/Metadone | Pain Intensity Measured by a Numeric Rating Scale (NRS) | NRS dynamic 24 hours | 3.13 units on NRS | Standard Deviation 2.2 |
| Zero/Metadone | Pain Intensity Measured by a Numeric Rating Scale (NRS) | NRS static 48 hours | 0.87 units on NRS | Standard Deviation 1.36 |
| Ketamine/Methadone | Pain Intensity Measured by a Numeric Rating Scale (NRS) | NRS dynamic 24 hours | 3.04 units on NRS | Standard Deviation 1.66 |
| Ketamine/Methadone | Pain Intensity Measured by a Numeric Rating Scale (NRS) | NRS static 48 hours | 0.5 units on NRS | Standard Deviation 0.88 |
| Ketamine/Methadone | Pain Intensity Measured by a Numeric Rating Scale (NRS) | NRS static 24 hours | 0.78 units on NRS | Standard Deviation 1.28 |
| Ketamine/Methadone | Pain Intensity Measured by a Numeric Rating Scale (NRS) | NRS dynamic 48 hours | 2.75 units on NRS | Standard Deviation 1.96 |