A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management

Imperial College London, Londinium, England, United Kingdom
Anesthesiology (Impact Factor: 6.17). 06/2006; 104(5):1040-6. DOI: 10.1097/00000542-200605000-00021
Source: PubMed

ABSTRACT 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.
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.
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.
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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Transcutaneous electrical nerve stimulation (TENS) is a non-pharmacological therapy for the treatment of pain. The present work investigated the effect of cannabidiol, naloxone and diazepam in combination with 10Hz and 150Hz TENS. Male Wistar rats were submitted to the tail-flick test (baseline), and each rodent received an acute administration (intraperitoneal) of naloxone (3.0mg/kg), diazepam (1.5mg/kg) or cannabidiol (0.75mg/kg, 1.5mg/kg, 3.0mg/kg, 4.5mg/kg, 6.0mg/kg and 12.0mg/kg); 10min after the acute administration, 10Hz or 150Hz TENS or a sham procedure was performed for 30min. Subsequently, tail-flick measures were recorded over a 90-min period, at 5-min intervals. 10Hz TENS increased the nociceptive threshold during the 90-min period. This antinociceptive effect was reversed by naloxone pre-treatment, was not altered by diazepam pre-treatment and was abolished by cannabidiol pre-treatment (1.5mg/kg). Moreover, 150Hz TENS increased tail-flick latencies by 35min post-treatment, which was partially inhibited by naloxone pre-treatment and totally inhibited by cannabidiol (1.5mg/kg). These data suggest the involvement of the endogenous opioid system and the cannabinoid-mediated neuromodulation of the antinociception induced by transcutaneous electrostimulation at 10Hz and 150Hz TENS.
    Journal of the Neurological Sciences 09/2014; 347(1-2). DOI:10.1016/j.jns.2014.09.024 · 2.26 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: AimTo evaluate the analgesic efficacy of AZD1940, a novel peripherally acting cannabinoid CB1/CB2 receptor agonist, in patients undergoing third molar surgical removal.Methods This was a randomized, double-blind, placebo-controlled study in patients scheduled for surgical removal of an impacted lower third molar. Patients received a single oral dose of 800 μg AZD1940, 500 mg naproxen or placebo 1.5 h before surgery. The dose of 800 μg AZD1940 was selected based on earlier data from a single dose study in man, in which it was identified as the highest well tolerated dose. Ongoing post-operative pain (primary variable) and pain on jaw movement were assessed on a visual analog scale (VAS, 0–100 mm) from 0 to 8 h postoperatively, deriving the area under the curve of ongoing pain (VAS AUC0–8 h), and of pain on jaw movement (VASJM AUC0–8 h). The time to requesting rescue medication (acetaminophen) was recorded. Subjective cannabinoid effects were assessed by the visual analog mood scale (VAMS).ResultsIn total, 151 patients were randomized to AZD1940 (n = 61), placebo (n = 59) or naproxen (n = 31). There was no statistically significant difference in pain VAS AUC0–8 h or in VASJM AUC0–8 h between AZD1940 and placebo. Naproxen significantly reduced both pain VAS AUC0–8 h and VASJM AUC0–8 h as compared with placebo (p < 0.0001 for both). Significantly fewer patients on naproxen requested rescue medication and the duration of time to rescue was greater, as compared with placebo, whereas there were no significant differences between AZD1940 and placebo in these outcome variables. Statistically significant increases in VAMS items “sedated” and “high” were observed after AZD1940 compared with placebo. The increases in VAMS were numerically small compared with previous findings with a centrally acting cannabinoid. The most commonly observed adverse events (AE) on treatment with AZD1940 were postural dizziness (80% of subjects), nausea (26%), hypotension (21%) and headache (13%), most AE being mild to moderate.Conclusion The CB1/CB2 receptor agonist AZD1940 did not reduce post-operative pain after lower third molar surgical removal at doses exerting subjective cannabinoid effects.ImplicationsActivation of peripheral CB1/CB2 receptors per se is probably of less clinical relevance for the treatment of acute nociceptive pain in man.
    Scandinavian Journal of Pain 01/2013; 4(1):17–22. DOI:10.1016/j.sjpain.2012.08.004
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Although medicinal cannabis has been used for many centuries, the therapeutic potential of delta-9-tetrahydrocannabinol (Δ9-THC; international non-proprietary name = dronabinol) in current pain management remains unclear. Several pharmaceutical products with defined natural or synthesized Δ9-THC content have been developed, resulting in increasing numbers of clinical trials investigating the analgesic efficacy of dronabinol in various pain conditions. Different underlying pain mechanisms, including sensitization of nociceptive sensory pathways and alterations in cognitive and autonomic processing, might explain the varying analgesic effects of dronabinol in chronic pain states. Areas covered: The pharmacokinetics, pharmacodynamics and mechanisms of action of products with a defined dronabinol content are summarized. Additionally, randomized clinical trials investigating the analgesic efficacy of pharmaceutical cannabis based products are reviewed for the treatment of chronic nonmalignant pain. Expert opinion: We suggest a mechanism-based approach beyond measurement of subjective pain relief to evaluate the therapeutic potential of dronabinol in chronic pain management. Development of objective mechanistic diagnostic biomarkers reflecting altered sensory and cognitive processing in the brain is essential to evaluate dronabinol induced analgesia, and to permit identification of responders and/or non-responders to dronabinol treatment.
    Expert Opinion on Pharmacotherapy 05/2014; DOI:10.1517/14656566.2014.918102 · 2.86 Impact Factor

Full-text (2 Sources)

Available from
May 30, 2014