Oncology

Chemotherapy-Induced Nausea and Vomiting

The Therapeutic Goods Administration (TGA) of Australia has prepared clinical guidance documents for prescribers of medicinal cannabis products for numerous conditions. A link to those guidance documents can be found here.

Summaries of clinical evidence that has been published since the release of the TGA’s guidance documents can be found below.

Efficacy and Expected Benefits

In recent years, particularly since medicinal cannabis products have become more available, there has been an increase in cannabis use in people suffering from chronic pain.1,2 The need to find alternatives to current analgesic options, particularly opioids, is another driver for research into cannabis products for chronic pain.1-3

Until 2017, available data on the use of cannabis products for treatment of chronic non-cancer pain (CNCP) was mainly from studies on synthetic Δ9-tetrahydrocannabinol (THC), standardised high-THC extracts, non-standardised (i.e., variable THC content) cannabis products (referred to as Cannabis sativa), or THC:CBD extracts.1,2 These cannabis products were associated with adverse events (AEs), including dizziness, nausea, drowsiness, effects on mood, cognition and attention. Until recently, there have been very few studies of the non-intoxicating cannabinoid, cannabidiol (CBD), for the treatment of CNCP.1-3

Large-scale, high quality, double-blind, randomised controlled trials (RCTs) are needed to establish the safety and efficacy of cannabis products for treating CNCP. The results of clinical studies to date are inconclusive, although there is some evidence of benefit. Long-term studies are needed to explore potential AEs associated with long-term medicinal cannabis use, which is currently poorly understood.1-3

Evidence Reviews

Therapeutic Goods Administration, 2017

Due to the level of interest in medicinal cannabis as a treatment for CNCP, the Therapeutic Goods Administration commissioned an expert team to systematically review the available evidence published between 1980 and early 2017.2

The evidence for effects of medicinal cannabis on change in pain intensity were assessed according to the following measures of improvement: meaningful (≥30%) and substantial (≥50%). Other important outcomes were physical and emotional functioning, patient global impression of change (PGIC), withdrawal from the study and AEs. In total, 102 studies investigating the effect of cannabis products on patients with CNCP were reviewed: 26 parallel group RCTs, 23 crossover RCTS, and 53 observational studies.2

A meta-analysis of all RCTs for CNCP found a moderate grade of evidence indicating that cannabis products (averaged across all products) were more likely than placebo to produce meaningful and substantial pain score reductions. However, when examined separately, the efficacy of nabiximols (Sativex®—a 1:1 ratio THC:CBD extract), Nabilone (synthetic THC) and ∆-9-tetrahydrocannabinol (THC) extract versus placebo was inconsistent. This is likely due to the small number of trials and small sample sizes. No RCTs were identified for CBD or CBD extract in this time period.2

Of the 53 observational studies identified, only 7 met the inclusion criteria of measuring pain outcomes and including a suitable comparator group. Of these, none examined 30% reduction in pain, and only one reported a 50% reduction in pain. This study found no significant evidence of benefit for THC extract, CBD extract, or THC:CBD extract compared to placebo. Nor was significant evidence of effect found in the remaining 6 studies which examined change in pain intensity (nabilone [n=3] and Cannabis sativa [n=3]). The evidence from all reviewed observational studies was considered to be of low quality.2

Studies also reported on physical functioning (n=49 studies), emotional functioning (n=39 studies) and participant ratings of global improvement and satisfaction with treatment (n=24 studies). Of these, the strongest evidence was for nabiximols (THC:CBD) leading to improvements in sleep and the PGIC (moderate grade evidence).2

Overall, medicinal cannabis appeared to be well tolerated by CNCP patients in the short term in the studies reviewed. Studies of AEs found that CNCP patients taking medicinal cannabis were 2.3 times more likely to experience an AE and 2.5 times the odds of a serious AE compared with those taking placebo. These odds were significantly influenced by single studies of synthetic THC and THC:CBD extracts. Serious AEs were reported in a smaller number of studies.2

Baron, 2018

This review assessed the use of cannabis products in the treatment of chronic pain from a range of causes, noting their potential role in combatting the opioid epidemic. It also assessed the major and minor cannabinoids, primary and secondary terpenes, and flavonoids. Noting the varying proportion of cannabinoids, terpenes, flavonoids, and other compounds across cannabis cultivars, Baron discussed how this can lead to synergistic benefits in whole plant extracts versus cannabis isolates, and produce wide variations in benefits and AEs between products.3 These synergies have been discussed previously and are known as ‘the
entourage effect’.4

Overall, Baron reviewed 39 RCTs and 7 observational studies with statistically significant positive outcomes. He concluded there is growing evidence for therapeutic benefits of cannabis products in many conditions, such as in the treatment of chronic pain, with promise for migraine and headache. Further research is needed to elucidate what are the most effective profiles of cannabinoids, terpenes, flavonoids, and other compounds for treating pain, as well as for other diseases and symptoms.3

Primary literature

Cunetti et al, 2018

Kidney transplant patients must limit their use of non-steroidal anti-inflammatory drugs (NSAIDs) for pain management due to the risk of nephrotoxicity, limiting their options for analgesia. There is evidence to suggest that modulation of the endocannabinoid system (ECS) may assist in the management of chronic pain, and therefore provides a rationale for the use of medicinal cannabis in patients suffering from chronic pain. This study assessed CBD due to its neuroprotective, antioxidant, anticonvulsant, analgesic, and anti-inflammatory effects, along with its favourable safety profile.5

The concomitant immunosuppressive agent taken by 5 of the 7 patients was tacrolimus, a more potent calcineurin inhibitor than cyclosporine, and hence a more potent inhibitor of T lymphocyte activation. Cyclosporine was taken by the remaining 2 patients. Due to the intra- and interindividual pharmacokinetic variability of calcineurin inhibitors, standard practice is to monitor clinical status and plasma markers of kidney transplant patients throughout their treatment. The study carefully evaluated clinically relevant pharmacokinetic interactions between CBD, an inhibitor of CYP3A4, and cyclosporine or tacrolimus which are CYP3A4 substrates.5

This 3-week study included seven patients with a mean age of 64.5 years (range, 58–75) who had received a kidney transplant ≥1 year previously and experienced uncontrolled chronic pain. An oral solution of a cannabis whole plant extract (50 mg/mL of CBD with a CBD:THC ratio of 30:1) was initiated at 50 mg BID (100 mg/day) and up-titrated to 150 mg BID (300 mg/day) over 3 weeks.5

Efficacy

Pain was assessed using a pain score index (reported scores ranging between 1 and 9) and patient perception of limitation (none, mild, moderate, or severe). Optimal pain control was achieved in 2 patients (osteoarticular pain [n=1] and neuropathic pain [n=1]). A partial response was achieved in 4 patients in the first 15 days, one of whom reported better pain control with lower CBD doses leading to a CBD dose reduction after day 21. One patient reported no change.5

Safety

No change in creatinine, full blood count, liver function tests, liver enzymes, or cyclosporine were found for any patient between baseline and day 21. Changes in tacrolimus levels were observed in patient 2 (decrease: 7.4 to 2.8 ng/mL) and patient 5 (increase: 7.8 to 13.8 ng/mL). These changes in tacrolimus levels were interpreted as probably due to intraindividual variability (level returned to normal 1 week later) and as a consequence of diabetic gastroenteropathy, respectively.5

Mild AEs were reported following CBD dose increases, which the authors suggest may have been avoided had the dose increases been more gradual. One patient developed persistent nausea that required a dose reduction on day 4. It was noted that this patient had a history of digestive intolerance to several other medications. The reported AEs were nausea, dry mouth, dizziness, drowsiness, and episodes of intermittent heat, all of which were self-limiting.5

Fleury-Teixeira et al, 2019

This retrospective, open-label, observational study investigated the effect of short-term treatment with CBD-enriched hemp oil, chosen for its effects on the ECS, which plays an important role in pain modulation. The objective was to alleviate symptoms and improve quality of life (QOL) in 21 females aged 12–24 years who developed serious AEs following human papillomavirus (HPV) vaccination, characterised by a severe somatoform and dysautonomic syndrome (asthenia, severe pain, skin rashes, sinus tachycardia, amenorrhea, optic neuritis, headache, sleep disturbances) and high titres of autoantibodies.6

The CBD-enriched hemp oil was administered sublingually to all patients, in some cases added to their baseline medication regimen. The starting dose of CBD for all patients was 25 mg per day in a twice-daily divided dose. This was up-titrated once each week by 2–5 mg CBD until intolerance or a maximum dose of 150 mg/mL CBD per day was achieved (weeks 6 and 7), the dose was then down-titrated weekly to the original daily dose of 25 mg at week 12.6

Efficacy

QOL was assessed using the Short Form-36 (SF-36) health questionnaire. After CBD treatment, 2 patients dropped out due to mild AEs, and 2 stopped treatment early due to lack of benefit. The SF-36 revealed significant benefits in the physical component score (P < .02), vitality (P < .03) and social role functioning (P < .02) post-treatment. Treatment also significantly reduced body pain according to the SF-36 assessment.6

Safety

CBD tolerability and AEs were assessed weekly during the 3-month treatment period. The CBD-rich hemp oil was found to be safe and generally well tolerated. The authors noted that RCTs are needed to better understand the safety and efficacy of this compound.6

It is worth noting that this study used hemp (seed) oil enriched with pure CBD,6 rather than a high-CBD whole plant extract, which might have conferred additional benefit due to entourage effects.4

Clinical Considerations

Dosing

In the absence of strong evidence for dosing and specific cannabis products in the treatment of CNCP, it is recommended that any healthcare practitioner choosing to administer cannabinoid therapy should assess response to treatment, effectiveness and adverse effects after 1 month.2

CBD

Three observational studies reporting CBD treatment in CNCP used the recommended clinical approach of up-titrating slowly from a low starting dose. Dosing of standardised CBD products (sublingual spray or oral capsule) ranged from 25–300 mg/day, and treatment duration was between 3 and 12 weeks.5-7

Cannabidiol: Tetrahydrocannabinol (CBD:THC), THC and Cannabis sativa

Daily doses in studies using THC:CBD products ranged from 2.7–130 mg THC and 2.5–120 mg CBD, with treatment duration from 2–14 weeks (RCTs) and 6–62 weeks (observational studies).2

Dosing for THC extracts (generally standardised products delivered as oral capsule or oromucosal spray) ranged between 2.5 and 130 mg daily. Treatment duration ranged from 2 days to 12 weeks (RCTs) and 2–20 weeks (observational studies).2

For synthetic THC products, doses were between 0.25 and 60 mg daily with treatment duration ranging between 1 day and 156 weeks (RCTs), and from 4 to 52 weeks (observational studies).2

References

  1. Boyaji S, Merkow J, Elman RNM, Kaye AD, Yong RJ, Urman RD. The Role of Cannabidiol (CBD) in Chronic Pain Management: An Assessment of Current Evidence. Curr Pain Headache Rep. Jan 24 2020;24(2):4. doi: 10.1007/s11916-020-0835-4
  2. Therapeutic Goods Administration. Guidance for the use of medicinal cannabis in the treatment of chronic non-cancer pain in Australia. 2017. https://www.tga.gov.au/publication/guidance-use-medicinal-cannabis-treatment-chronic-non-cancer-pain-australia
  3. Baron EP. Medicinal Properties of Cannabinoids, Terpenes, and Flavonoids in Cannabis, and Benefits in Migraine, Headache, and Pain: An Update on Current Evidence and Cannabis Science. Headache. Jul 2018;58(7):1139-1186. doi: 10.1111/head.13345
  4. Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. Aug 2011;163(7):1344-1364. doi: 10.1111/j.1476-5381.2011.01238.x
  5. Cunetti L, Manzo L, Peyraube R, Arnaiz J, Curi L, Orihuela S. Chronic Pain Treatment With Cannabidiol in Kidney Transplant Patients in Uruguay. Transplant Proc. Mar 2018;50(2):461-464. doi: 10.1016/j.transproceed.2017.12.042
  6. Palmieri B, Laurino C, Vadala M. Short-Term Efficacy of CBD-Enriched Hemp Oil in Girls with Dysautonomic Syndrome after Human Papillomavirus Vaccination. Isr Med Assoc J. Feb 2017;19(2):79-84. PMID: 28457055
  7. Notcutt W, Price M, Miller R, et al. Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 ’N of 1’ studies. Anaesthesia. May 2004;59(5):440-452. doi: 10.1111/j.1365-2044.2004.03674.x

Abbreviations

AE, adverse event;
CBD, cannabidiol;
CNCP, chronic non-cancer pain;
ECS, endocannabinoid system;
PGIC, patient global impression of change;
QOL, quality of life;
SF-36, Short Form-36;
THC, ∆-9-tetrahydrocannabinol.