Safety, and Tolerability of THC:CBD Extract in Patients with Intractable Cancer-Related Pain

Abstract

This study compared the efficacy of a tetrahydrocannabinol:cannabidiol(THC:CBD) extract, a nonopioid analgesic endocannabinoid system modulator, and a THC extract, with placebo, in relieving pain in patients with advanced cancer. In total, 177 patients with cancer pain, who experienced inadequate analgesia despite chronic opioid dosing, entered a two-week, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial. Patients were randomized to THC:CBD extract (n = 60), THC extract (n = 58), or placebo (n = 59). The primary analysis of change from baseline in mean pain Numerical Rating Scale (NRS) score was statistically significantly in favor of THC:CBD compared with placebo (improvement of −1.37 vs. −0.69), whereas the THC group showed a nonsignificant change (−1.01 vs. −0.69). Twice as many patients taking THC:CBD showed a reduction of more than 30% from baseline pain NRS score when compared with placebo (23 [43%] vs. 12 [21%]). The associated odds ratio was statistically significant, whereas the number of THC group responders was similar to placebo (12 [23%] vs. 12 [21%]) and did not reach statistical significance. There was no change from baseline in median dose of opioid background medication or mean number of doses of breakthrough medication across treatment groups. No significant group differences were found in the NRS sleep quality or nausea scores or the pain control assessment. However, the results from the European Organisation for Research and Treatment of Cancer Quality of Life Cancer Questionnaire showed a worsening in nausea and vomiting with THC:CBD compared with placebo (P = 0.02), whereas THC had no difference (P = 1.0). Most drug-related adverse events were mild/moderate in severity. This study shows that THC:CBD extract is efficacious for relief of pain in patients with advanced cancer pain not fully relieved by strong opioids.


Cancer pain is a common problem, and 70%–90% of patients with advanced cancer experience significant pain.1 Opioids remain the keystone for the treatment of moderate to severe cancer pain; however, some patients experience inadequate pain relief with opioids and standard adjuvant analgesics despite dose adjustments, and unacceptable side effects are common.

Cannabis contains 60 or more cannabinoids (CBs). The main ones include delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD).4, 5 There is evidence that both THC and CBD show promise in relieving cancer-related pain.6, 7 Sativex®(THC:CBD), an endocannabinoid system modulator, is produced by GW Pharma Ltd, United Kingdom. It is derived from strains of Cannabis sativa L. plants developed to produce high and reproducible yields of principal CBs (THC and CBD), with minor amounts of other CBs and terpenes in a solution containing ethanol, propylene glycol, and peppermint oil flavoring.5 The named CBs constitute at least 90% of the total CB content of the extracts.

CBs act primarily through specific CB receptors: CB1 receptors are predominantly distributed in the central nervous system, and CB2 receptors are located primarily in the periphery (including the immune system). The principal pharmacological effects of THC include analgesia, muscle relaxation, antiemesis, appetite stimulation, and psychoactivity.8 CBD has shown anticonvulsant, muscle relaxant, anxiolytic, neuroprotective, antioxidant, and antipsychotic activity, and has been also shown to reduce the anxiety and psychoactive effects of THC.9, 10 Preliminary tests of pharmacology and behavioral activity support the similarity of the endogenous CB anandamide to THC.11 Both are partial agonists at the CB1receptor. CBD, in contrast, binds weakly to CB1 and CB2 but does show pharmacological potency as a neutral antagonist at each receptor,12 that is, is silent at such receptors but can reverse both agonist and inverse agonist responses. CBD also has shown powerful anti-inflammatory, immunomodulatory,13 and antioxidant properties in vitro.14 It is a TRPV1 vanilloid receptor agonist in its own right, while modulating anandamide by inhibiting both its reuptake and hydrolysis.15Additionally, CBD increases adenosine A2A receptor signaling by inhibition of the adenosine transporter.16 Both THC and CBD have shown analgesic efficacy in animal models.10, 17, 18 In this study, both a THC:CBD extract and a THC-only extract were compared against placebo to ascertain if the inclusion of CBD provided a different efficacy or safety profile.

Campbell et al.19 published a literature review of nine randomized controlled trialsperformed using CBs (any route of administration) in patients with acute, chronic nonmalignant, or cancer pain. Five studies that were described in four reports comprised 128 patients with cancer pain.6, 7, 20, 21 All of the trials conducted in patients with cancer pain were placebo-controlled trials. Four of the trials found CB as effective as codeine but with dose-limiting side effects. Thus, CBs have demonstrated efficacy comparable to selected opioids.

THC:CBD is the first endocannabinoid system modulator to undergo clinical development for pain. It has been approved in Canada for the relief of neuropathic pain in multiple sclerosis and persistent background cancer-related pain. The formulation is an oromucosal spray that allows flexible, individualized dosing. Patients self-titrate their overall dose and pattern of dosing according to their response to, and tolerance of, the medicine, with administration of approximately 8–12 sprays/day, that is, 22–32 mg/day THC and 20–30 mg/day CBD. This study assessed the analgesic efficacy of THC:CBD and THC extracts compared with that of placebo in the management of patients with at least moderately severe cancer-related pain despite appropriate pharmacological management.Methods This two-week (two-day baseline and two-week treatment), multicenter, double-blind, randomized, placebo-controlled, parallel-group study evaluated the efficacy of THC:CBD extract and THC extract in the analgesic management of patients with moderate to severe cancer-related pain. There was a two-day baseline period. Adult male or female patients who had been using strong opioids for at least one week to relieve pain associated with incurable malignancy and who gave written informed consent were screened for study entry. Eligible patients recorded a pain severityscore of 4 or above on a 0–10 Numerical Rating Scale (NRS) on both days of the two-day baseline period. Patients were excluded if they had cancers affecting the oral cavity; radiotherapy to the floor of the mouth; major psychiatric or cardiovascular disorders; epilepsy; renal or hepatic impairment; or if they were pregnant, lactating, or not using adequate contraception. Patients who had received therapies expected to confound the study outcome (epidural analgesia within 48 hours of screening; palliative radio-, chemo-, or hormonal therapy within two weeks of screening; or CBs within seven days of randomization) were also excluded. Patients taking levodopa, sildenafil, or fentanyl or patients with a hypersensitivity to CBs were excluded on safety grounds. Patients completed a study diary, recording pain score three times daily and background medication and all additional breakthrough analgesia on each day during the baseline period. Patients then returned for assessment, randomization, and dose introduction to one of the three treatment arms: THC:CBD extract, THC extract, or placebo (Fig. 1) in a 1:1:1 treatment allocation ratio. Patients were reviewed after 7–10 days (Visit 2) and at the end of study (14–20 days) or withdrawal (Visit 3). During the medication dosing period, the patients continued to complete the daily study diaries with the aforementioned information and the number of doses of study medication taken. The relevant regulatory authorities and research ethics committees approved the study. The study medication was delivered using a pump action oromucosal spray. Each 100-μL actuation of the pump containing the THC:CBD extract delivered a dose containing 2.7 mg THC and 2.5 mg CBD. Each 100-μL actuation of the pump containing the THC extract delivered a dose containing 2.7 mg THC, and each actuation of placebo delivered only excipients plus colorants. The maximum permitted dose of all study medication was eight actuations in any three-hour period and 48 actuations in any 24-hour period.

Patients self-titrated to their optimal dose over the seven days of Week 1, based on efficacy, tolerability, and the maximum permitted dose. Patients could increase the total number of sprays each day by a maximum of 50% until they either had satisfactory relief of their symptoms or developed unwanted effects, such as intoxication (“high”). The total number of sprays was spread over the day with a minimum of 15 minutes between any two sprays. If unwanted effects developed on a new number of sprays, the patient would not take any further sprays for three to four hours. The patient would then go back to taking their further sprays at a similar level to the previous day. Once the patient had found the maximum number of sprays per day that they tolerated well or the number that provided good symptom relief, they continued with approximately the same number of sprays per day for the remainder of the study.

The coprimary endpoints were the change from baseline in NRS pain score and use of breakthrough analgesia. The NRS, a widely used and validated measure of pain severity, is capable of showing clinically and statistically significant changes in pain disorders.22, 23 The NRS question “indicate your level of pain” was answered by patients three times daily (in the morning on waking, at lunchtime, and in the evening before retiring), using the anchors 0 = no pain and 10 = very bad pain. Patients were allowed to use their breakthrough analgesia as required, and this was recorded daily in the diary. Patients maintained background medication for the duration of the study. The secondary endpoints included the use of opioid background medication, patient assessments of sleep quality, nausea, memory, concentration, and appetite over the previous 24 hours using diary NRSs. The Brief Pain Inventory-Short Form (BPI-SF) and The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) Version 3 were completed by patients at Visit 1 and at the end of the study.24, 25The BPI-SF consists of nine questions; eight have a single response, and Question 9 is subdivided into seven parts. The Total BPI (Questions 3–6) is the unweighted sum of the four pain scores and represents the pain intensity. The Total BPI for Question 9 is the unweighted sum of the seven assessments and represents the effect of pain. The EORTC QLQ-C30 cancer questionnaire consists of 30 questions that cover global health status, functional scales (e.g., physical functioning), and symptoms (e.g., fatigue).

Adverse events (AEs) and use of concomitant medications were reported by patients at study visits throughout the trial. Predefined categories for determining the intensity and the relationship to study medication were used. The expert clinical judgment from the investigating study physicians was used in determining intensity and causal relationship of AEs and serious AEs.

The study was powered assuming an underlying treatment difference of 1 point on an NRS and a standard deviation (SD) of 1.6 (estimated from previous studies), with 80% power and two-sided 5% significance.26, 27 After allowing for 15% dropouts, 58 subjects per group were required. For the two coprimary efficacy variables (NRS pain score and use of breakthrough medication), the Hochberg28 method was used to test the global hypothesis for a treatment effect on pain. The null hypothesis was to be rejected if either coprimary variable produced two-sided P ≤ 0.025 or both produced P ≤ 0.05. The daily pain NRS score was the mean of the three daily assessments. The change in mean NRS pain score from baseline (all days in run-in period) to the end of treatment (last three days on treatment) was analyzed using analysis of covariance (ANCOVA), with baseline pain as a covariate and grouped study center and treatment as factors.29, 30 The proportions of responders (patients with ≥30% improvement from baseline to end of study NRS pain score) were compared between treatments. Use of breakthrough medication (number of days of use during last three days on treatment) was analyzed using logistic regression with a cumulative logit model. In addition, the change from baseline in mean number of doses of escape medication was analyzed using ANCOVA.


Results

A total of 192 patients were screened over 25 months, leading to 177 patients randomized to treatment (Fig. 1) at 28 European centers. The mean (SD) duration of cancer in these patients was 3.5 years (2.8 [3.27], 3.2 [4.27], and 4.5 [5.25] years, respectively, in the THC:CBD, THC, and placebo groups, respectively). The mean age, gender distribution, previous cannabis use, primary disease sites, and pain classification were similar among the three treatment groups (Table 1). The most common type of cancer pain was of mixed pathophysiology, followed by bone and neuropathic pain (Table 1). At baseline, the mean daily dose of opioid background medication in the whole study population was 271 mg of oral morphine equivalents. The median oral morphine equivalent dose was slightly lower in the THC:CBD group at baseline compared with the THC and placebo groups (Table 2). For all three treatment groups, the predominant primary reason for discontinuing the study was AEs (Fig. 1). The mean (SD) number of sprays taken per day, which had stabilized by the end of the first week (Days 1–7) ending the titration phase, were THC:CBD extract, 8.75 (5.14); THC extract, 8.34 (5.17); and placebo, 9.61 (4.67) (Fig. 2). Overall, for the entire treatment period, the mean (SD) number of sprays used daily in the placebo group (10.88 [5.81]) was higher than those in the THC:CBD (9.26 [5.53]) and THC groups (8.47 [5.46]).

Fig. 2. Exposure to study medication—mean number of sprays per day. SE = standard error. Efficacy The mean (SD) baseline NRS pain scores were similar among treatment groups and within grouped centers (THC:CBD extract = 5.68 [1.24], range = 2.33–8.25; THC extract = 5.77 [1.33], range = 2.87–9.33; placebo = 6.05 [1.32], range = 3.5–9.56). The adjusted mean reduction in NRS (ANCOVA) for THC:CBD, THC, and placebo groups at the end of the treatment were −1.37, −1.01, and −0.69 points, respectively.31 The adjusted mean treatment difference from placebo was statistically significant for a reduction in pain with the THC:CBD extract (0.67 points, P = 0.014) but not the THC extract (0.32 points, P = 0.245). The ANCOVA did not have normally distributed residuals, but the nonparametric analysis gave a similar result. The median changes from baseline for THC:CBD, THC, and placebo groups were −1.36, −1.00, and −0.60, respectively. The median difference from placebo was statistically significant for a reduction in pain, which was in favor of THC:CBD extract (0.55 points, P = 0.024) but not for the THC extract (0.24 points, P = 0.204). Sensitivity analyses of the change from baseline in the mean NRS scores concurred with the primary analysis. In chronic pain trials, it is recommended that the percentages of patients obtaining reductions in pain intensity of at least 30% on a pain NRS (responders) should be documented.32 A reduction in pain NRS of approximately 30% is considered to represent a clinically important difference.23 In the intent-to-treat responder analysis, approximately twice as many patients in the THC:CBD group had a reduction from baseline NRS of at least 30% compared with the placebo and THC groups (THC:CBD = 23 [43%] vs. THC = 12 [23%], placebo = 12 [21%]). The odds ratio for the comparison of responders between THC:CBD and placebo was 2.81 (95% confidence interval [CI] = 1.22, 6.50; P = 0.006), and between THC and placebo was 1.10 (95% CI = 0.44, 2.73; P = 0.28) (Fig. 3).

Fig. 3. Pain 0–10 Numerical Rating Scale scores: responder analysis (ITT analysis). aOdds ratio (95% CI) THC:CBD vs. placebo; bFisher’s exact test. The number of days on which any breakthrough medication was used was similar among all treatment groups, with no significant differences observed in this clinical trial of brief duration (THC:CBD vs. placebo: P = 0.70). There was a reduction observed in the mean number of daily doses of all breakthrough medication (THC:CBD extract = −0.19; THC extract = −0.14; placebo = −0.15) by the end of the study period, but the difference in change from baseline between treatment groups was not statistically significant. More specifically, there was no change from baseline to the last three days of treatment in the median oral morphine equivalent dose of opioid background medications in 124 (78%) patients for whom the data were available. Doses were increased for 16 patients (10%) and reduced for 18 (11%); these changes were evenly distributed across the three treatment groups (Table 2). During the baseline period or last three days on treatment, strong opioid breakthrough medication was recorded by 59 patients (33%); of these, 34 (58%) showed no change in the number of doses taken when comparing baseline with last three days of treatment, 13 (22%) increased the number of doses, and 12 (20%) reduced the number of doses taken. A greater proportion of patients in the THC:CBD group (eight patients) reduced breakthrough doses; conversely, the highest proportion of increases in dose was in the placebo group (seven patients), which was statistically significantly greater than those in the THC:CBD group (P = 0.004). Most of the NRS diary symptom scores and investigator-assessed pain control showed no significant treatment differences between the three groups (Table 3<