A Multicenter Dose-Escalation Study Of The Analgesic And Adverse Effects

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Abstract
Background: Cannabinoids have dose-related antinociceptive effects in animals. This clinical study aimed to investigate whether a single oral dose of cannabis plant extract (Cannador; Institute for Clinical Research, IKF, Berlin, Germany) could provide pain relief with minimal side effects for postoperative pain.

Methods: Patients (aged 18—75 yr) were recruited and consented before surgery if patient-controlled analgesia was planned for provision of postoperative pain relief. Each patient received a single dose of 5, 10, or 15 mg Cannador if he or she had at least moderate pain after stopping patient-controlled analgesia. Starting with 5 mg, dose escalation was based on the number of patients requesting rescue analgesia and adverse effects. Pain relief, pain intensity, and side effects were recorded over 6 h and analyzed using tests for trend with dose.
Results: Rescue analgesia was requested by all 11 patients (100%) receiving 5 mg, 15 of 30 patient (50%) receiving 10 mg, and 6 of 24 patients (25%) receiving 15 mg Cannador (log rank test for trend in time to rescue analgesia with dose P < 0.001). There were also significant trends across the escalating dose groups for decreasing pain intensity at rest (P = 0.01), increasing sedation (P = 0.03), and more adverse events (P = 0.002). The number needed to treat to prevent one rescue analgesia request for the 10-mg and 15-mg doses, relative to 5 mg, were 2.0 (95% confidence interval, 1.5—3.1) and 1.3 (95% confidence interval, 1.1—1.7), respectively. The study was terminated because of a serious vasovagal adverse event in a patient receiving 15 mg.

Conclusion: These significant dose-related improvements in rescue analgesia requirements in the 10 mg and 15 mg groups provide a number needed to treat that is equivalent to many routinely used analgesics without frequent adverse effects.

ACUTE pain after surgery remains a therapeutic problem because many of the commonly used drugs prove inadequate through lack of efficacy or side effects. Newer analgesic products are being developed through an in-depth understanding of the neurochemical systems involved in pain processing1,2 including the endocannabinoid system.3 Selective cannabinoid agonists have been demonstrated to suppress nociceptive transmission in spinal cord, periaqueductal gray, and thalamus in a dose-related manner.1 Exogenous cannabinoids have been tested in clinical trials in chronic pain disorders such as visceral pain,4 neuropathic pain,5—10 and multiple sclerosis.11—13 Results vary with the clinical setting, possibly because of the diversity of psychological and pathologic processes in chronic pain states. In postoperative pain, there are fewer effects of chronic disease, but more heterogeneity in patient conditions. However, a recent meta-analysis concluded that if specific standards were met, such as at least moderate pain to enter a study, a 6-h study duration, and avoidance of bias, then a study combining different surgical interventions could provide a high-level evidence base for analgesic response.14

Clinical trials of analgesic drugs have studied single cannabinoids such as synthetic δ-9-tetrahydrocannabinol (THC, dronabinol), ajulemic acid (CT-3), or cannabis extracts containing phytocannabinoid mixtures such as THC and cannabidiol. The advantages of ajulemic acid and cannabidiol are a lack of affective side effects and the potential for antiinflammatory activity.10,15 For postoperative pain, a THC—cannabidiol mixture offers the potentially distinctive role of analgesia and antiinflammatory effects as well as relief of muscle spasm, reduction of nausea and vomiting, and appetite stimulation. It may thus support postsurgical recovery without adverse effects such as respiratory depression, renal failure, or gastrointestinal ulceration.

Results from the few clinical trials addressing the use of cannabinoids for acute postoperative pain have been mixed. No analgesic effects were reported from a randomized, double-blind, crossover study of 10 males who each received intravenous placebo, diazepam, or two doses of THC for dental extraction pain.16 In a randomized, placebo-controlled trial of 56 postsurgical or trauma patients, the cannabinoid levonantradol provided non—dose-dependent pain relief, but adverse side effects limited further study.17 More recently, THC, either as a capsule (in a randomized, placebo-controlled, double-blind trial) or sublingual spray (dose-escalation study), has been reported to have no analgesic effects at 5 mg after abdominal hysterectomy.18 However, higher doses of THC were effective in the treatment of cancer pain.19

This study was designed to test whether a standardized cannabis plant extract was analgesic in the context of acute pain after surgery. We chose to deliver a single dose because clinical effects from the oral route can last as long as conventional oral analgesics, i.e., up to 6 h.

Source: A Multicenter Dose-escalation Study of the Analgesic and Adv... : Anesthesiology