3.6 | Quality of life
Given the complex presentation of the cohort of patients under investigation, we report the EORTC-QLQ-30 scores (Figure 6) for those patients diagnosed with breast and prostate cancer with metastasis to the bone versus those of the whole cohort.
There was an overall improvement from baseline for global health status; physical functioning; emotional functioning; cognitive functioning; fatigue; pain; dyspnoea and insomnia (Figure 6). Participants diagnosed with cancer metastatic to bone reported similar trends to the whole cohort
(Figure 6). The threshold for clinical significance was only achieved for emotional functioning, fatigue, dyspnoea, insomnia and appetite loss.
| Discussion
Quality of life measures in this SAD MAD study met the primary endpoint of safety and tolerability. The study demonstrated that the administration of the investigative medicine (NanaBisTM) was generally safe in a cohort of chronically ill patients diagnosed with advanced cancers with intractable pain despite opioid treatment. Moreover, results from patient-reported outcome questionnaires suggest that patient functioning (e.g., physical, social, emotional and cognitive) improved clinically for emotional functioning, fatigue, dyspnea, insomnia and appetite loss.
The water-soluble nanoparticle cannabis formulation has appropriate pharmacokinetics of cannabinoids for a maintenance analgesic, with peak plasma concentration in less than an hour and efficacy durable enough to support dosing every four hours (with multiple dosing). Oromucosal delivery using 50% ethanol (and propylene glycol) [23] does not seem to be as effective as the nanoparticle water-soluble spray. For example, comparing the PK data with that reported for an ethanol-based Δ9-THC/CBD spray, NanaBisTM achieved an approximate equivalent AUC(0-t) and Cmax with half the Δ9-THC/CBD administered dose. The ethanol-based spray (5.4 mg Δ9-THC/5.4 mg CBD) reported mean AUC(0-t) and Cmax of 2.99/0.82 ng mL.h−1 and 1.48/0.39 ng mL−1 respectively [23]. A comparison with half the dose from NanaBisTM 2.5 mg Δ9-THC/2.5 mg CBD), the calculated means for AUC(0-t) and Cmax were 2.79/1.46 ng mL.h−1 and 1.58/1.02 ng mL−1 respectively. Furthermore, the nanoparticle water-soluble delivery technology provided one peak consistent with mostly mucosal delivery, whereas 50% ethanol provided two peaks and inconsistent serum levels [23], indicating inefficient mucosal absorption with substantial swallowing of the medicine and less effective gastrointestinal absorption. The NanoCelleTMdelivery platform also avoids the local and systemic adverse effects of ethanol and propylene glycol [29].
There is significant interest in the use of cannabis for the management of chronic cancer pain or non-cancer pain [30, 31] irrespective of any adverse outcomes that have been reported. As yet, there is minimal evidence on the prevalence or predictors for adverse events in people administered cannabis [32]. In recreational users of cannabis, coughing fits, anxiety and paranoia were the most common adverse reactions [32]. In the clinical trial setting, oral, gastrointestinal or sublingual administered cannabis, was associated with nausea, fatigue, vertigo/hallucinations, diarrhoea, constipation and dry mouth [11, 33-36]. In our study, the administration of a nanoparticle water soluble cannabis-based medicine resulted in mild drowsiness, fatigue, nausea and vomiting. Drug tolerability was established at 2-8 sprays, namely 2.5 mg to 10 mg each of Δ9-THC and CBD every 4 hours, which reported no evidence that the cannabis formulation increased the risk of serious adverse events. An independent safety monitoring panel concluded at the end of Stage I of this study, that there were no safety issues that would impede continued development of the study’s cannabis-based medicine. The oro-buccal delivered cannabis-based medicine administered as a water-soluble nanoparticle is of significant clinical interest given that this formulation was a self-titrated medicine, that showed preliminary analgesic efficacy in a subgroup of patients.
There are clearly however, limitations to this study. The sample was small with an open label pilot design with no comparator that included only patients with advanced cancer, with intractable pain unrelieved by opioids. There was a substantial variation in eligible patient cancer diagnoses that produced a largely heterogenous study group. Furthermore, patients presented with multiple and overlapping types of pain.
In this cohort of patients with complex advanced cancers the adverse events encountered were similar to those commonly reported from other studies that have administered a cannabis-based medicine [37]; with the most common being drowsiness, fogginess, fatigue, nausea and vomiting. The level of emetogenicity in cancer varies based on different factors and the incidence in this study was 36%. In 8 (32%) patients that developed nausea, the causal attribution was probably / possible associated with the administered cannabis-based medicine. In 6 (24%) patients though, vomiting was concomitantly reported with nausea, with one patient reporting persistent nausea and vomiting that interrupted the further administration of the cannabis-based medicine. Notwithstanding this study of single and multiple cannabis doses that were oro-buccal administered, demonstrated an overall safety and tolerance profile.
Various clinical investigations with administered cannabis-based medicines via the gastrointestinal tract have reported limited tolerability and efficacy in a variety of indications [38]. Furthermore, the frequency of delivery and the magnitude of exposure to a drug can also influence the abuse potential and safety profile.
Numerous animal [39-41] and human studies [42-44] have reported the synergistic analgesic effects of concomitant administration of opioids and cannabinoids. In our study, patients reported significant improvement in pain scores over the course of the intervention phase of the study of approximately 12% (p=0.02). Notwithstanding, all patients diagnosed with bone metastasis reported a significant reduction in pain scores at the end of the treatment phase. In participants with a diagnosis of metastatic breast and prostate cancers (only to bone) had a highly significant reduction in pain scores (adjusted for rescue medications) of 33% (unadjusted of 40%) during the escalation and treatment phases (p<0.01) with minimal mean increases in MMeq and rescue medications as compared to the cohort overall.
Although this SAD MAD study was not placebo controlled, the improvement in pain was consistent with a recent systematic and meta-analysis that concluded that cannabis-based medicines probably increase the number of people achieving pain relief of 30% or greater compared with placebo. The pain relief was reversed on cessation of administration of the investigated medicine. In the metastatic breast and prostate cancer group cessation of NanaBisTM use resulted in a decrease in pain relief efficacy of 13%.
5 | Conclusions
This report described a single ascending dose / multiple ascending dose of a water-soluble
Δ9-THC/CBD nanoparticle formulation administered to advanced cancer patients with intractable pain as a co-analgesic. The oro-mucosal administration of this formulation at doses from 2.5 mg to 10 mg per 4 hours of Δ9-THC and CBD (unless asleep) was found to be safe and tolerable.
There was an overall significant improvement in average NPRS pain scores over the study treatment period from baseline. There was however a significant improvement in pain recorded over the treatment period for all patients diagnosed with bone metastasis. The significant improvement in average adjusted NPRS pain scores of 33% as recorded for an eligible subgroup of participants with a diagnosis of breast and prostate cancers with metastatic disease (only to bone). This may partly be due to the superior delivery method that the NanoCelleTM platform of the cannabis-based medicine provides, as well as the cancer pain subgroup of metastatic bone pain.
Author Contributions: Conceptualisation, SC AJM, LV, SH; methodology, SC, AJM, BB, LV; formal analysis, BB, LV, AJM; investigation, SC; resources, SC, LV, SH; data curation, BB, AJM, LV; writing—original draft preparation, LV, JDH, SH; writing—review and editing, SC, LV, AJM, BB JDH, DR, SH.; project administration, LV, SH; funding acquisition, SH. All authors have read and agreed to the published version of the manuscript
Conflicts of Interest: JDH DR SH and LV are employed by Medlab Clinical Australia and participate in its cannabis-based medicines research program. BB is an independent statistician who was funded by Medlab Clinical Ltd Australia to conduct the statistical analysis.
Acknowledgments: We acknowledge the assistance of Serena Dal Forno RN, Jillian Bethwaite RN.
Funding: This research was funded by Medlab Clinical Ltd. Australia.
References
1. Bonini SA, Premoli M, Tambaro S, Kumar A, Maccarinelli G, Memo M, Mastinu A. Cannabis sativa: A comprehensive ethnopharmacological review of a medicinal plant with a long history. J Ethnopharmacol 2018; 227: 300-15.
2. Fraguas-Sanchez AI T-SA. Medical Use of Cannabinoids. Drugs 2018; 78: 1665-703.
3. ElSohly MA, Radwan MM, Gul W, Chandra S, Galal A. Phytochemistry of Cannabis sativa L. Prog Chem Org Nat Prod 2017; 103: 1-36.
4. Borgelt LM, Franson KL, Nussbaum AM, Wang GS. The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy 2013; 33: 195-209.
5. Ibeas Bih C, Chen T, Nunn AV, Bazelot M, Dallas M, Whalley BJ. Molecular Targets of Cannabidiol in Neurological Disorders. Neurotherapeutics 2015; 12: 699-730.
6. Boehnke KF, Gangopadhyay S, Clauw DJ, Haffajee RL. Qualifying Conditions Of Medical Cannabis License Holders In The United States. Health Aff (Millwood) 2019; 38: 295-302.
7. Mucke M, Phillips T, Radbruch L, Petzke F, Hauser W. Cannabis-based medicines for chronic neuropathic pain in adults. The Cochrane database of systematic reviews 2018; 3: Cd012182.
8. Aviram J, Samuelly-Leichtag G. Efficacy of Cannabis-Based Medicines for Pain Management: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Pain Physician 2017; 20: E755-e96.
9. Yanes JA, McKinnell ZE, Reid MA, Busler JN, Michel JS, Pangelinan MM, Sutherland MT, Younger JW, Gonzalez R, Robinson JL. Effects of cannabinoid administration for pain: A meta-analysis and meta-regression. Exp Clin Psychopharmacol 2019; 27: 370-82.
10. Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, Donaghe H. Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain 2013; 14: 136-48.
11. Mucke M, Weier M, Carter C, Copeland J, Degenhardt L, Cuhls H, Radbruch L, Hauser W, Conrad R. Systematic review and meta-analysis of cannabinoids in palliative medicine. J Cachexia Sarcopenia Muscle 2018; 9: 220-34.
12. Ware MA, Wang T, Shapiro S, Robinson A, Ducruet T, Huynh T, Gamsa A, Bennett GJ, Collet JP. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. Cmaj 2010; 182: E694-701.
13. Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, Kelly ME, Rowbotham MC, Petersen KL. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology 2007; 68: 515-21.
14. Ellis RJ, Toperoff W, Vaida F, van den Brande G, Gonzales J, Gouaux B, Bentley H, Atkinson JH. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology 2009; 34: 672-80.
15. Sohler NL, Starrels JL, Khalid L, Bachhuber MA, Arnsten JH, Nahvi S, Jost J, Cunningham CO. Cannabis Use is Associated with Lower Odds of Prescription Opioid Analgesic Use Among HIV-Infected Individuals with Chronic Pain. Subst Use Misuse 2018; 53: 1602-07.
16. National Academies of Sciences E, Medicine, Health, Medicine D, Board on Population H, Public Health P, Committee on the Health Effects of Marijuana: An Evidence R, Research A. The National Academies Collection: Reports funded by National Institutes of Health. In: The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research, Washington (DC): National Academies Press (US) 2017 by the National Academy of Sciences. All rights reserved.
17. Boland EG, Bennett MI, Allgar V, Boland JW. Cannabinoids for adult cancer-related pain: systematic review and meta-analysis. BMJ Support Palliat Care 2020; 10: 14-24.
18. Russo EB. Cannabis and Pain. Pain Med 2019; 20: 2083-85.
19. Huestis MA, Henningfield JE, Cone EJ. Blood cannabinoids. I. Absorption of THC and formation of 11-OH-THC and THCCOOH during and after smoking marijuana. J Anal Toxicol 1992; 16: 276-82.
20. Brown JD. Potential Adverse Drug Events with Tetrahydrocannabinol (THC) Due to Drug-Drug Interactions. J Clin Med 2020; 9.
21. Bruni N, Della Pepa C, Oliaro-Bosso S, Pessione E, Gastaldi D, Dosio F. Cannabinoid Delivery Systems for Pain and Inflammation Treatment. Molecules 2018; 23.
22. Giesinger JM, Loth FLC, Aaronson NK, Arraras JI, Caocci G, Efficace F, Groenvold M, van Leeuwen M, Petersen MA, Ramage J, Tomaszewski KA, Young T, Holzner B. Thresholds for clinical importance were defined for the European Organisation for Research and Treatment of Cancer Computer Adaptive Testing Core-an adaptive measure of core quality of life domains in oncology clinical practice and research. J Clin Epidemiol 2020; 117: 117-25.
23. Stott CG, White L, Wright S, Wilbraham D, Guy GW. A phase I study to assess the effect of food on the single dose bioavailability of the THC/CBD oromucosal spray. Eur J Clin Pharmacol 2013; 69: 825-34.
24. Ferreira JA. The Benjamini-Hochberg method in the case of discrete test statistics. Int J Biostat 2007; 3: Article 11.
25. Hochberg Y TA. Multiple Comparison Procedures. New York: Wiley and Sons 1987.
26. Afifi AAA, S.P. . Statistical Analysis: A Computer Oriented Approach. 2nd Edition. New York.: Academic Press, 1979.
27. Frayers PM AN, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf of the EORTC Quality of Life Group. . The EORTC QLQ-30 scoring manual (3rd edition) European Organisation for Research and Treatment of Cancer: Brussels. 2001.
28. Chang A, Schyve PM, Croteau RJ, O’Leary DS, Loeb JM. The JCAHO patient safety event taxonomy: a standardized terminology and classification schema for near misses and adverse events. Int J Qual Health Care 2005; 17: 95-105.
29. Scully C. Cannabis; adverse effects from an oromucosal spray. Br Dent J 2007; 203: E12; discussion 336-7.
30. Haroutounian S, Ratz Y, Ginosar Y, Furmanov K, Saifi F, Meidan R, Davidson E. The Effect of Medicinal Cannabis on Pain and Quality-of-Life Outcomes in Chronic Pain: A Prospective Open-label Study. Clin J Pain 2016; 32: 1036-43.
31. Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, Keurentjes JC, Lang S, Misso K, Ryder S, Schmidlkofer S, Westwood M, Kleijnen J. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. Jama 2015; 313: 2456-73.
32. LaFrance E. M. S, A., Glodosky, N. C., Mauzay, D.,Cuttler, C. . Overbaked: assessing and predicting acute adverse reactions to Cannabis. Journal of Cannabis Research 2020; 2: 3.
33. Blake A, Wan BA, Malek L, DeAngelis C, Diaz P, Lao N, Chow E, O’Hearn S. A selective review of medical cannabis in cancer pain management. Ann Palliat Med 2017; 6: S215-s22.
34. Boychuk DG, Goddard G, Mauro G, Orellana MF. The effectiveness of cannabinoids in the management of chronic nonmalignant neuropathic pain: a systematic review. J Oral Facial Pain Headache 2015; 29: 7-14.
35. Fallon MT, Albert Lux E, McQuade R, Rossetti S, Sanchez R, Sun W, Wright S, Lichtman AH, Kornyeyeva E. Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies. Br J Pain 2017; 11: 119-33.
36. Hauser W, Welsch P, Klose P, Radbruch L, Fitzcharles MA. Efficacy, tolerability and safety of cannabis-based medicines for cancer pain : A systematic review with meta-analysis of randomised controlled trials. Schmerz 2019; 33: 424-36.
37. Patti F, Messina S, Solaro C, Amato MP, Bergamaschi R, Bonavita S, Bruno Bossio R, Brescia Morra V, Costantino GF, Cavalla P, Centonze D, Comi G, Cottone S, Danni M, Francia A, Gajofatto A, Gasperini C, Ghezzi A, Iudice A, Lus G, Maniscalco GT, Marrosu MG, Matta M, Mirabella M, Montanari E, Pozzilli C, Rovaris M, Sessa E, Spitaleri D, Trojano M, Valentino P, Zappia M. Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity. J Neurol Neurosurg Psychiatry 2016; 87: 944-51.
38. Killestein J, Hoogervorst EL, Reif M, Kalkers NF, Van Loenen AC, Staats PG, Gorter RW, Uitdehaag BM, Polman CH. Safety, tolerability, and efficacy of orally administered cannabinoids in MS. Neurology 2002; 58: 1404-7.
39. Bushlin I, Rozenfeld R, Devi LA. Cannabinoid-opioid interactions during neuropathic pain and analgesia. Curr Opin Pharmacol 2010; 10: 80-6.
40. Smith FL, Cichewicz D, Martin ZL, Welch SP. The enhancement of morphine antinociception in mice by delta9-tetrahydrocannabinol. Pharmacol Biochem Behav 1998; 60: 559-66.
41. Welch SP, Stevens DL. Antinociceptive activity of intrathecally administered cannabinoids alone, and in combination with morphine, in mice. J Pharmacol Exp Ther 1992; 262: 10-8.
42. de Vries M, Van Rijckevorsel DC, Vissers KC, Wilder-Smith OH, Van Goor H. Single dose delta-9-tetrahydrocannabinol in chronic pancreatitis patients: analgesic efficacy, pharmacokinetics and tolerability. Br J Clin Pharmacol 2016; 81: 525-37.
43. Lichtman AH, Lux EA, McQuade R, Rossetti S, Sanchez R, Sun W, Wright S, Kornyeyeva E, Fallon MT. Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as an Adjunctive Therapy in Advanced Cancer Patients with Chronic Uncontrolled Pain. J Pain Symptom Manage 2018; 55: 179-88.e1.
44. Nurmikko TJ, Serpell MG, Hoggart B, Toomey PJ, Morlion BJ, Haines D. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain 2007; 133: 210-20.
Table 1: Patient baseline demographic and clinical characteristics for Stage I and Stage II.