Morphine Versus Ketamine as Adjuvants in Paravertebral Blocks (Annie-Dimitr)

• ClinicalTrials.gov Identifier: NCT04852484
• Recruitment Status: Active, not recruiting
• First Posted: April 21, 2021
• Last Update Posted: April 22, 2021
• Sponsor: Aretaieion University Hospital
• Collaborator: KAT General Hospital
• Information provided by (Responsible Party): Dr Kassiani Theodoraki, Aretaieion University Hospital

Tracking Information

• First Submitted Date: April 16, 2021
• First Posted Date: April 21, 2021
• Last Update Posted Date: April 22, 2021
• Actual Study Start Date: April 16, 2021
• Estimated Primary Completion Date: April 16, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 16, 2021)

morphine consumption in the first 48 hours [ Time Frame: 48 hours postoperatively ]

patients will be followed for cumulative morphine consumption through patient-controlled analgesia device for 48 hours postoperatively

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 16, 2021)

• morphine consumption in Post-Anesthesia Care Unit (PACU) [ Time Frame: 24 hours postoperatively ]
  mg of morphine requested during patient PACU stay
• pain score on arrival to Post-Anesthesia Care Unit (PACU) [ Time Frame: immediately postoperatively ]
  pain score by the use of Numeric Rating Scale (NRS) on arrival to PACU, ranging from 0 to 10, where 0 means "no pain" and 10 means "worst pain imaginable"
• pain score 6 hours postoperatively [ Time Frame: 6 hours postoperatively ]
  pain score by the use of Numeric Rating Scale (NRS) 6 hours postoperatively, ranging from 0 to 10, where 0 means "no pain" and 10 means "worst pain imaginable"
• pain score 12 hours postoperatively [ Time Frame: 12 hours postoperatively ]
  pain score by the use of Numeric Rating Scale (NRS) 12 hours postoperatively, ranging from 0 to 10, where 0 means "no pain" and 10 means "worst pain imaginable"
• pain score 24 hours postoperatively [ Time Frame: 24 hours postoperatively ]
  pain score by the use of Numeric Rating Scale (NRS) 24 hours postoperatively, ranging from 0 to 10, where 0 means "no pain" and 10 means "worst pain imaginable"
• pain score 48 hours postoperatively [ Time Frame: 48 hours postoperatively ]
  pain score by the use of Numeric Rating Scale (NRS) 48 hours postoperatively, ranging from 0 to 10, where 0 means "no pain" and 10 means "worst pain imaginable"
• morphine consumption in the first 6 hours [ Time Frame: 6 hours postoperatively ]
  patients will be followed for cumulative morphine consumption through patient-controlled analgesia device for 6 hours postoperatively
• morphine consumption in the first 12 hours [ Time Frame: 12 hours postoperatively ]
  patients will be followed for cumulative morphine consumption through patient-controlled analgesia device for 12 hours postoperatively
• morphine consumption in the first 24 hours [ Time Frame: 24 hours postoperatively ]
  patients will be followed for cumulative morphine consumption through patient-controlled analgesia device for 24 hours postoperatively
• side effects postoperatively [ Time Frame: 96 hours postoperatively ]
  patients will be monitored for side-effects of the administered agents postoperatively
• satisfaction from postoperative analgesia [ Time Frame: 48 hours postoperatively ]
  satisfaction from postoperative analgesia on a four-point Likert scale with 1 marked as minimal satisfaction and 4 as maximal satisfaction
• morphine requirement during surgery [ Time Frame: intraoperatively ]
  dose of required morphine administered intraoperatively
• time to first request for analgesia [ Time Frame: during stay in Post-Anesthesia Care Unit, 24 hours postoperatively ]
  the time for the first patient request for analgesia will be noted
• hospitalization time [ Time Frame: 7 days postoperatively ]
  duration of hospital stay after surgery in days
• incidence of chronic pain 3 months after surgery [ Time Frame: 3 months after surgery ]
  occurrence of chronic pain at the site of the operation 3 months after surgery, with the use of the Numeric Rating Scale (NRS), at rest and during movement
• incidence of chronic pain 6 months after surgery [ Time Frame: 6 months after surgery ]
  occurrence of chronic pain at the site of the operation 6 months after surgery, with the use of the Numeric Rating Scale (NRS), at rest and during movement

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Morphine Versus Ketamine as Adjuvants in Paravertebral Blocks
• Official Title: Morphine Versus Ketamine as Adjuvants in Ultrasound-guided Paravertebral Thoracic Blocks in Elective Thoracic Surgery
• Brief Summary: The aim of this study will be to compare the effects of morphine versus ketamine when they are used as adjuvants to the local anesthetic in paravertebral nerve blocks performed with the aid of ultrasound. Furthermore, a group of local anesthetic without an adjuvant, will also be compared to the two groups

Detailed Description

Elective thoracotomies are usually performed for removal of pathological masses in the mediastinum, lung parenchyma and upper gastrointestinal system. They are considered to be painful operations, related to both acute and chronic pain (post- thoracotomy pain syndrome), the latter lasting for a minimum period of 2 months.

Post-operative thoracic pain is associated often with diaphragmatic dysfunction, which can also lead to atelectasis and pneumonia and post-operative pulmonary complications in general.

Several techniques have been tried in order to minimize such events. Thoracic epidural analgesia, intravenous analgesia, intercostal blocks, local infiltration of local anesthetics by the surgeon are some of them.

Paravertebral thoracic blocks have become increasingly popular in recent years since they are less likely to cause neurologic complications than thoracic epidural analgesia. Moreover, bleeding disorders, and use of anti-coagulant and anti- thrombotic medications, which are considered as contraindications to an epidural procedure, are not strict contraindications in the performance of paravertebral blocks, especially when they are performed under ultrasonographic guidance.

Ropivacaine and Levobupivacaine are the most popular local anesthetics that have been used. Moreover, several adjuvants have been added to them in order to enhance the effects of those blocks. Dexamethasone, Morphine, Dexmedetomidine, Clonidine, Ketamine, Magnesium Sulphate are some of them. Results are variable.

The rationale behind adjuvants used to enhance effects of local anesthetics is the fact that some seem to act directly in the spinal cord receptors and the central nervous system. The effect of morphine on the dorsal horns of the spinal cord has been extensively studied in the past. Due to its limited lipophilicity, it is assumed that administering the specific drug to the paravertebral space could lead to its transfer and action on the dorsal horns.

On the other hand, the action of ketamine seems to be by blocking N-Methyl-D-Aspartate (NMDA) receptors in the spinal cord. It is also considered to have an effect on voltage sensitive Ca2+ channels, opioid receptors, and monoaminergic receptors. Therefore, it is considered overall to affect nociception.

Overall, it is assumed that morphine might have an effect on the dorsal horns of the spinal cord, and ketamine on NMDA receptors at "higher pain centers". It is also assumed that there will be some degree of systemic absorption due to the rich vascular supply of the specific area. The investigators aim to compare the effects of those two when they are used as adjuvants to the local anesthetic in paravertebral nerve blocks performed with the aid of ultrasound. Furthermore, a group of local anesthetic without an adjuvant, will also be compared.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention

Condition

• Pain, Postoperative
• Pain, Acute
• Pain, Chronic
• Pain, Neuropathic
• Morphine
• Ketamine
• Analgesia

Intervention

• Drug: local anesthetic-morphine
  Before the operation, 19 mL of 0.5% Ropivacaine + 2 mg of morphine (20 mL in total) will be injected in the paravertebral space. Afterwards, there will be a pump of 500 ml of 0.2 % ropivacaine + 6 mg of morphine connected to the catheter after the end of the surgery, administered continuously at a rate of 10 mL/hr
  Other Name: local anesthetic and morphine administered paravertebrally
• Drug: local anesthetic-ketamine
  Before the operation, 19 mL of 0.5% Ropivacaine + 50 mg of ketamine (20 mL in total) will be injected in the paravertebral space. Afterwards, there will be a pump of 500 ml of 0.2 % ropivacaine + 200 mg of ketamine connected to the catheter after the end of the surgery, administered continuously at a rate of 10 mL/hr
  Other Name: local anesthetic and ketamine administered paravertebrally
• Drug: local anesthetic
  Before the operation, 19 mL of 0.5% Ropivacaine + 1 mL of normal saline (20 mL in total) will be injected in the paravertebral space. Afterwards, there will be a pump of 500 ml of 0.2 % ropivacaine connected to the catheter after the end of the surgery, administered continuously at a rate of 10 mL/hr
  Other Name: local anesthetic administered paravertebrally

Study Arms

• Active Comparator: local anesthetic and morphine group
  paravertebral block with local anesthetic and morphine, followed by a continuous infusion of local anesthetic and morphine in the paravertebral space
  Intervention: Drug: local anesthetic-morphine
• Active Comparator: local anesthetic and ketamine group
  paravertebral block with local anesthetic and ketamine, followed by a continuous infusion of local anesthetic and ketamine in the paravertebral space
  Intervention: Drug: local anesthetic-ketamine
• Active Comparator: local anesthetic group
  paravertebral block with local anesthetic only, followed by a continuous infusion of local anesthetic only in the paravertebral space
  Intervention: Drug: local anesthetic

Publications *

• Gerner P. Postthoracotomy pain management problems. Anesthesiol Clin. 2008 Jun;26(2):355-67, vii. doi: 10.1016/j.anclin.2008.01.007. Review.
• D'Ercole F, Arora H, Kumar PA. Paravertebral Block for Thoracic Surgery. J Cardiothorac Vasc Anesth. 2018 Apr;32(2):915-927. doi: 10.1053/j.jvca.2017.10.003. Epub 2017 Oct 4. Review.
• El Mourad MB, Amer AF. Effects of adding dexamethasone or ketamine to bupivacaine for ultrasound-guided thoracic paravertebral block in patients undergoing modified radical mastectomy: A prospective randomized controlled study. Indian J Anaesth. 2018 Apr;62(4):285-291. doi: 10.4103/ija.IJA_791_17.
• Ahmed MJ, Ur Rehman A, Arshad RM, Amjad MWA, Khan Z, Furqan A. Efficacy of Dexmedetomidine vs Morphine as an Adjunct in a Paravertebral Block with Bupivacaine in Postoperative Analgesia Following Modified Radical Mastectomy. Cureus. 2020 May 22;12(5):e8231. doi: 10.7759/cureus.8231.
• Mao Y, Zuo Y, Mei B, Chen L, Liu X, Zhang Z, Gu E. Efficacy of perineural dexamethasone with ropivacaine in thoracic paravertebral block for postoperative analgesia in elective thoracotomy: a randomized, double-blind, placebo-controlled trial. J Pain Res. 2018 Sep 11;11:1811-1819. doi: 10.2147/JPR.S164225. eCollection 2018.
• Maruyama Y, Shimoji K, Shimizu H, Sato Y, Kuribayashi H, Kaieda R. Effects of morphine of human spinal cord and peripheral nervous activities. Pain. 1980 Feb;8(1):63-73. doi: 10.1016/0304-3959(80)90090-1.
• Kathirvel S, Sadhasivam S, Saxena A, Kannan TR, Ganjoo P. Effects of intrathecal ketamine added to bupivacaine for spinal anaesthesia. Anaesthesia. 2000 Sep;55(9):899-904.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: April 16, 2021): 90
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: April 16, 2023
• Estimated Primary Completion Date: April 16, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• patients undergoing elective thoracotomy for any cause
• American Society of Anesthesiologists class I-III (ASA I-III)

Exclusion Criteria:

• known allergy to local anesthetic
• local inflammation
• paravertebral tumor
• severe respiratory distress ( breathing dependence on accessory muscles)
• severe spinal deformities
• severe ipsilateral diaphragmatic paresis
• morbid obesity (BMI>35 kg/m2)
• blood coagulation disorders
• known contraindication for administration of ketamine or morphine
• psychiatric disorders
• severe cardiovascular disease
• systematic use of opioids due to chronic pain
• renal or hepatic failure
• patients who refuse to participate

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 25 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Greece

Administrative Information

• NCT Number: NCT04852484
• Other Study ID Numbers: 307/26-03-2021
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Dr Kassiani Theodoraki, Aretaieion University Hospital
• Study Sponsor: Aretaieion University Hospital
• Collaborators: KAT General Hospital

Investigators

• Principal Investigator: Kassiani Theodoraki, PhD, DESA; Aretaieion University Hospital

• PRS Account: Aretaieion University Hospital
• Verification Date: April 2021