ABSTRACT
AIM: This study aimed to assess the pharmacokinetics, tolerability, safety and exploratory analgesic efficacy of a novel water-soluble oro-buccal nanoparticle spray of a cannabis-based medicine in advanced cancer patients with unrelieved pain.
METHODS: The study was a non-blinded single arm, single escalating dose (n=5) [2.5 mg Δ9-THC and 2.5 mg CBD) and multiple escalating doses (up to 5.5 doses)] of a two-stage pilot study in patients diagnosed with advanced cancers and intractable pain (n=25).
RESULTS: As the cannabis-based medicine dose increased, maximum observed plasma concentrations of all analytes were approximately proportional to dose. The bioavailability of Δ9-THC and CBD in this water-soluble nanoparticle formulation was approximately twice the bioavailability reported for a Δ9-THC/CBD formulation with ethanol. The water-soluble formulation in the current study resulted in a higher median (min, max) bioavailability of Δ9-THC than CBD (AUC from 2.5 mg each of Δ9-THC and CBD was 1.71 ng mL.h−1 (1.1, 6.6) and 0.65 ng mL.h−1 (0.49. 4.1), respectively). Analyte accumulation was not observed. In a subgroup of patients diagnosed with breast and prostate cancer with bone metastases, mean pain scores improvement from baseline was 40% (unadjusted) and 33% adjusted for rescue medication use. For all patients the most commonly reported adverse events were mild or moderate drowsiness affecting 11 (44%) and 4 (6%) patients, respectively and nausea and vomiting that affected 18 (72%) patients.
CONCLUSIONS: The water-soluble cannabis-based medicine (NanaBisTM) provided acceptable bioavailability for Δ9-THC/CBD, appeared safe and tolerable in cancer with uncontrolled pain with preliminary evidence of analgesic efficacy.
| Introduction
The dried leaves of the Cannabis sativa L. plant have long been used for both medicinal and recreational purposes [1, 2].Cannabis sativa L. contains a number of chemical compounds, some of which are classified as cannabinoids. Phytochemistry studies ofCannabis sativa L. has identified several medically useful components including the psychoactive cannabinoid tetrahydrocannabinol (Δ9-THC), the non-psychoactive cannabinoids such as cannabidiol (CBD), cannabichromene (CBC), and cannabigerol (CBG), and many non-cannabinoid constituents that belong to diverse classes of natural products [3]. Two major types of cannabinoid receptors have been characterised, namely CB1 and CB2 [3, 4]; however, Δ9-THC and CBD exert therapeutic effects via several other targets[5]. Given these varied pharmacological targets, it is not surprising that Δ9-THC and CBD induce varying pharmacologic responses depending on the formulation, dose and patient characteristics [4].
Relief from chronic pain (cancer or non-cancer related) is a common condition cited by patients for the medical use of cannabis [6, 7]. A recent systematic review and meta-analysis of 43 randomized controlled trials (RCTs) suggested that cannabis-based-medicines could be effective for chronic pain treatment and primarily for neuropathic pain [8]. Others have reported that cannabinoid-based pharmacotherapies may serve as effective replacement/adjunctive analgesic options [9].
Most of the studies that have investigated cannabis for analgesia have concentrated on those with neuropathic pain. For example, low dose Δ9-THC (1.29%) as vaporized cannabis was better for relieving central or peripheral neuropathic pain that was resistant to standard treatments compared to placebo [10]. Studies with oral / oromucosal routes of administration of cannabis as herbal crude or dry leaf cannabis extracts or synthetics of THC (dronabinol, nabilone) and plant-derived extracts of Δ9-THC/CBD oromucosal spray (nabiximols) formulations have also shown efficacy in chronic neuropathic pain [11]. The number needed to benefit (NNTB) for patients taking medicinal cannabis for chronic neuropathic pain was calculated in a Cochrane review as 11 to 20 (95% CIs 7-100), although clinical study sample sizes were small and lacking high-level evidence [7]. All cannabis-based-medicines pooled together were also better than placebo in reducing sleep problems and improving psychological distress and health related quality of life [7]. Medicinal cannabis may also be effective for other types of pain. Studies of smoked cannabis in postsurgical or post-traumatic pain [12] and in painful human immunodeficiency virus (HIV)-associated neuropathy [13-15] have reported efficacy over placebo in relieving pain, as well as being well tolerated [13].
Although, the effectiveness of medicinal cannabis for chronic pain has been established [16], all five previous clinical trials of medicinal cannabis for cancer pain (as reviewed by Boland et al [17] have failed to reach the efficacy endpoint. Oral administration of cannabis-based medicines with gastrointestinal absorption leads to highly variable systemic concentrations of pharmacologically active constituents leading to slow and erratic an onset of action for analgesic use [18]. Inhaled cannabis requires too frequent dosing for a maintenance analgesic as its half-life is less than 20 minutes [18, 19]. Furthermore, the high THC blood concentration (20- to 30-fold higher Cmax) after inhalation administration is associated with treatment limiting acute adverse effects and long-term damage from toxic chemicals associated with smoking or vaporizing [18] (high temperatures involved with vaporized cannabis can oxidize the medicine and excipients) [20].
The unsatisfactory nature of oral and inhaled administration routes for medicinal cannabis has led to additional proposed routes of administration such as transdermal and intranasal modes of delivery [21]. However, due to the lipophilic nature of cannabinoid molecules, drug delivery remains a challenge. Given that cannabinoids show promise, a feasible path toward highly regulated prescribed medicines is encouraged [21]. NanoCelleTM is an innovative nanoparticle delivery method that is ideal for improving the mucous membrane absorption of small lipid soluble molecules, such as the cannabinoid molecules Δ9-THC and CBD. The aim of this study was to investigate the safety, tolerability and preliminary efficacy in a two-dose approach pharmacokinetic investigation of an oro-buccal water-soluble nanosized delivered cannabis-based medicine containing a mixture of Δ9-THC/CBD in advanced cancer outpatients with uncontrolled pain who self-administered NanaBisTM.
  1. | Material and Methods
  2. | Study Design
This study consisted of two stages, namely: Stage I was a two-day single ascending dose (SAD) pharmacokinetic / pharmacodynamic investigation of the nanoparticle Δ9-THC/CBD formulation in five participants diagnosed with advanced cancer. On day 1 all participants were administered 2.5 mg Δ9-THC and 2.5 mg of CBD in 300 µL (two actuations of the pump) to the oro-buccal mucosa. On day 2 all subjects administered 7.5 mg of Δ9-THC and 7.5 mg of CBD in 900 µL (six actuations of the pump). Blood samples were collected at 0, 30, 60, 90, 120, 150, 180, 240, 360 minutes and 24 hours after dose administration via indwelling cannula.
Stage II was a multiple ascending dose (MAD) pilot study of 25 eligible participants with advanced cancer and uncontrolled pain that participated over three phases in a 30-day period. The three phases in Stage II were divided into a dose escalation phase over days 1 to 9; a treatment phase over days 10 to 15; and a follow-up phase over days 16 to 30. Prospective participants for the dose escalation phase were patients with incurable cancer attending the Royal North Shore Hospital Medical Oncology unit (North Sydney Local Health District Human Research Ethics Approval number: RESP/16/341 on 16th June 2017). For the second phase, patients from the first cohort were included if they had pain uncontrolled by opioid analgesics. Screening visits occurred −2 to 0 days prior to commencing administration of the Δ9-THC/CBD water soluble nanoparticle oro-buccal spray (Supplement 1). All participants commenced dose escalation, treatment and follow-up phases of Stage II (Figure 1). However only n=22 of 25 patients completed all phases of Stage II. The Stage II dose escalation phase timeline is presented in Figure 1. In the treatment phase, patients administered to their oral cavity (to the inside of a cheek) one, two or three actuations (sprays) every four hours (unless asleep) for six days. The dose to be administered was dependent on the safe and tolerable dose administered in the previous dose escalation phase of the study, as directed by the Principal Investigator (oncologist). In the follow-up phase, all patients were observed for the next 15 days after treatment cessation. Subsequently, for patients who reported significant benefit, in the treatment phase compassionate access to ongoing medicinal cannabis was provided. Plasma samples were collected prior to the first morning administration on days 1, 4, 7, 10, 13, 16 and 30.