In a phase 2 study, researchers found no difference between a delta-9-tetrahydrocannabinol (THC) tablet and a placebo tablet in reducing pain measures in patients with chronic abdominal pain from pancreatitis or surgery.
Chronic abdominal pain is frequently caused by chronic pancreatitis (CP) or surgery (called post-surgical pain). Pharmacologic agents that produce analgesia by targeting changes in the central nervous system are required.
THC is the principal psychoactive compound of the Cannabis sativa plant; it interacts with the cannabinoid receptors CB1 and CB2. CB1 receptors are predominantly found in the brain and spinal cord, and CB2 receptors are located primarily in the periphery, including the immune system. THC might interefere with sensory processes and nervous system circuits that determine pain.
Most clinical trials on the efficacy of THC for pain treatment have focused on cancer-related pain, central neuropathic pain syndromes, and acute pain conditions. Marjan de Vries et al performed clinical trials of the efficacy, pharmacokinetics, and safety of an oral tablet containing purified natural THC in 65 patients with persistent postsurgical abdominal pain and in patients with chronic pancreatitis and persistent abdominal pain.
Sixty-five patients with chronic abdominal pain for 3 months or more were randomly assigned to groups given the THC tablet or identical matching placebos for 50–52 days. Subjects in the THC group were given the tablet first in a step-up phase (3 mg 3 times daily for 5 days and then 5 mg 3 times daily for 5 days), followed by a stable dose phase (8 mg 3 times daily until days 50–52). Preceding and during the entire study period, patients were asked to continue taking their medications (including analgesics) according to prescription. The primary end point was pain relief, which was measured by a visual analogue scale (VAS).
At days 50–52, VAS mean scores did not differ significantly between the THC and placebo groups. Between the start and end of the study, VAS mean scores decreased by 1.6 points (40%) in the THC group compared with 1.9 points (37%) in the placebo group.
No statistically significant differences were observed in responses to pain-related questionnaires such as the patient global impression of change, pain catastrophizing, or pain-related anxiety. Measures of depression and generalized anxiety, quality of life, and treatment satisfaction did not change after THC treatment compared with placebo.
Oral THC was generally well absorbed. Seven patients in the THC group stopped taking the tablets because of adverse events, compared with 2 patients in the placebo group. All these events were mild or moderate.
de Vries et al say that insufficient analgesic potency of the investigational drug could be the reason the clinical trial did not demonstrate analgesic efficacy. However, the lack of effect could also be related to impaired bioavailability, a large placebo response (37% pain reduction in the placebo group), indirect analgesic effects, or inadequate study design.
The authors point out that most participants in the study had already had received different pain treatments, including analgesics, that failed to provide pain relief. So this study included a selection of patients who did not respond to registered analgesics with a proven efficacy.
They conclude that THC treatment showed acceptable safety and tolerability profiles during a 50-day to 52-day add-on treatment period but did not significantly reduce pain scores or secondary efficacy outcomes in patients with chronic abdominal pain compared with placebo. Further research should evaluate the effects of THC on secondary and tertiary central pain processing.
At the end of the video abstract, Harry van Goor says “We were surprised by the results of this study. We will not follow up this phase 2 study with a phase 3 study because we do not believe that in a larger population, this drug will show efficacy in a difficult to treat patient group with chronic abdominal pain”.