Perioperative Δ9-THC for Postsurgical Pain

Phase 2

• Conditions: Pain
• Interventions: Drug: Diazepam/placebo; Drug: Namisol

• Registration Number: NCT01790555
• Lead Sponsor: Radboud University Medical Center

Brief Summary

Adequate treatment of postsurgical pain leads to better mobilization, shorter hospital stay, lower costs and higher patient satisfaction. In its treatment, frequent use is made of opioids. However, opioids have many side-effects. A possible add-on can be sought in THC, which has been shown to have possible analgesic and/or pain modulating effects in preclinical research. The purpose of this study is to investigate the analgesic and pain modulating effects of perioperative Namisol, a tablet containing THC, in patients that will undergo major abdominal surgery.

Detailed Description

Rationale: Early postsurgical pain is a consequence of tissue trauma during surgery, which can lead to hyperalgesia or allodynia. Adequate management of postsurgical pain leads to earlier mobilization, shortened hospital stay, reduced costs, and increased patient satisfaction. Treatment usually involves the use of opioids, which have many side effects. Besides the problem of acute surgical pain, surgery may lead to the development of persistent postsurgical pain.

Based on preclinical research, it is hypothesized that Δ9-THC may improve outcomes of early postsurgical pain due to pain modulatory effects and may lower the incidence of persistent postsurgical pain through modulation of central pain processing, e.g. reduction of central sensitization. From clinical studies, evidence for the value of Δ9-THC in this context is, to date, scarce. Indeed, research in a patient group with a major nociceptive load - i.e. major abdominal surgery - and an extended perioperative treatment schedule has not been performed so far. Both a major nociceptive load and an extended perioperative treatment schedule are necessary for adequate assessment of the analgesic efficacy of Δ9-THC in this context. Thus, the question regarding the perioperative analgesic efficacy of Δ9-THC in major abdominal surgery remains unresolved.

Objectives: The primary aim of this study is to investigate the analgesic effect of perioperatively administered Namisol® to reduce postsurgical pain on the day of major abdominal surgery and in the first five days after major abdominal surgery. A secondary aim is to investigate the effect of perioperatively administered Namisol® on the incidence of persistent postsurgical pain in the first 12 postoperative weeks.

Study design: A randomized, double-blind, placebo-controlled, parallel-group study design with an perioperative add-on treatment of Namisol or placebo and a follow-up period of 24 weeks.

Study population: Forty patients will be recruited from the outpatient clinic of the department of surgery of the Radboud University Nijmegen Medical Center. Patients will have persistent or intermittent abdominal pain, due to underlying intra-abdominal pathology including diverticulitis, Crohn's disease, chronic pancreatitis, ulcerative colitis, endometriosis, or abdominal adhesions. Other intra-abdominal pathology may be included if causing pain and if judged appropriate by the investigator. Patients will be planned to undergo elective, open abdominal surgery with planned use of an epidural catheter for perioperative analgesia. The surgical procedure will have an estimated duration of at least two hours, excluding the time to induce anesthesia.

Intervention: Namisol®, a tablet with standardized Δ9-THC content, or identical matching placebos will be administered orally to evaluate the analgesic properties of Namisol® administered as add-on perioperative treatment. The study medication is given from the day before surgery (day -1: 5 mg in the afternoon and in the evening) up to the fifth day after surgery (day 0 to +5: 5 mg four times daily).

Primary and secondary study parameters: The primary study outcome is postsurgical pain intensity during the first five postoperative days, reflected by the primary endpoint: the area under the curve of the VAS scores in the first five days (AUC5days) after surgery. The secondary outcome is the incidence of persistent postsurgical pain 12 weeks after surgery.

Other study parameters: In addition to the primary and secondary outcomes, several other outcome parameters will be collected. These include measures of postsurgical pain intensity at 24 weeks after surgery, measures of analgesic efficacy (postoperative consumption of other analgesics), central nervous system processing and sensitization in the first 5 days and after 6 and 12 weeks after surgery (QST, Von Frey testing, and brush stroke testing), postoperative sedation level (Ramsay Scale), and immune system response during 72 hours after surgery and after 6 weeks (ILs, MMPs) are investigated. In addition, questionnaires are filled out to examine parameters related to side effects and postoperative recovery (VAS Bond\&Lader, VAS Bowdle, HADS, SF-36, PCS, PASS, QoR-40, AppLe, and TSQM). Two variants in genetic CYP2C9 polymorphisms will be genotyped and three variants in genetic CYP2C19 polymorphisms will be genotyped.

Nature and extent of the burdens, risks, and benefits: Participation means three or four visits to the outpatient clinic in addition to usual care, including the screening visit. Various measurements, including blood samples (seven additional samples over the entire study period), will be conducted during each visit. The participating patients may experience better pain relief in the postoperative period and may benefit from a reduced incidence of persistent postsurgical pain, but are subject to more intense diagnostics and observation.

Study Timeline

• Status Verified: 2013-02
• Study First Submitted: 2013-02-07
• Study First Submitted QC: 2013-02-11
• Study First Posted: 2013-02-13
• Study Start: 2013-07
• Primary Completion: 2013-10
• Last Update Submitted: 2013-10-22
• Last Update Posted: 2013-10-23
• Study Completion: 2014-04

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Diazepam/Placebo	Diazepam/placebo	The study medication is given from the day before surgery (day -1: 5 mg in the afternoon and in the evening) up to the fifth day after surgery (day 0 to +5: 5 mg four times daily). Before surgery, diazepam is used as an active comparator, to aid in blinding. After surgery, an inactive placebo is used as an inactive comparator.
Namisol	Namisol	The study medication is given from the day before surgery (day -1: 5 mg in the afternoon and in the evening) up to the fifth day after surgery (day 0 to +5: 5 mg four times daily).

Primary Outcome Measures

Name	Time	Method
Analgesic efficacy	Daily until +5 days after surgery	To investigate the analgesic efficacy of perioperative Namisol® for postsurgical pain at the day of surgery and in the first 5 days after abdominal surgery. Analgesic efficacy is measured as the difference in visual analog scale (VAS) area under the curve (AUC) for the day of surgery and the first 5 postoperative days between placebo and Namisol®.

Secondary Outcome Measures

Name	Time	Method
Incidence of persistent continuous or intermittent postsurgical abdominal pain	12 weeks after surgery	To investigate the effect of perioperative Namisol® for the incidence of persistent continuous of intermittent postsurgical abdominal pain 12 weeks after abdominal surgery.

Trial Locations

Locations (1)

Radboud University Nijmegen Medical Center; 🇳🇱 Nijmegen, Gelderland, Netherlands