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All participants, caregivers, investigators and clinical staff will remain blind to study assignment until trial completion. The code will only be broken in cases of a clinical emergency. An investigator not directly involved in the randomisation of patients will keep a blinded copy of the randomisation schedule and will be contacted in the event of the need to un-blind. All study drugs and placebo will be in oil solution form and identical in appearance. All oil solutions will be matched for taste, colour and bottle size to preserve the blinding irrespective of the contents, each participant will receive the oil solution in a prepacked bottle labelled with their individual trial participation ID number, and consecutively numbered according to the randomisation scale.

ALCTRN12618001220257 Registered 20/07/2018.

There is little high quality evidence of benefit to date for the use of medicinal cannabinoids. The most recent review from the USA National Academies of Sciences, Engineering, and Medicine found evidence for the use of medicinal cannabinoids for treatment of some types of chronic pain, CINV and spasticity in multiple sclerosis in some patients, with moderate evidence for sleep disorders [10]. Cannabinoid products are licensed for a range of conditions in different countries, with little consistency between countries for indication and dosing [11]. Whilst cannabinoids may have potential clinical benefits, their use is not without possible adverse effects and further research is needed define their role in medical practice [3, 11].

Methods

Participants must have a negative pregnancy urine test at eligibility (only if of reproductive potential) and agree to avoid pregnancy during the study and 12 weeks following the last dose of the study drug. Males must agree to avoid fathering a child and to not donate sperm during the study and for at least 12 weeks following the last dose of the study drug. Further to this the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) [15] will be conducted to determine eligibility. It is designed to determine whether harmful substance are being used and go undetected or become worse. The assessment is comprised of 8 questions assessing, tobacco, alcohol, cocaine, amphetamine-type stimulants, sedatives, hallucinogens, opiates and ‘other drugs’.

Cannabis contains more than 500 bioactive compounds, including more than seventy different cannabinoids [5]. The main cannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is thought to be the main psychoactive component of cannabinoids Potential benefits of THC can include pain control,, nausea improvement, and relaxation of muscles with potential side effects including psychosis, sedation and intoxication. The recommended dose range for oral THC varies from 2.5 to 40 mg/day [6]. CBD is not intoxicating, and in animals has demonstrated some benefits in anxiety, psychosis, inflammation, epilepsy and demonstrated neuroprotective effects [7]. CBD is also considered to mediate many of the adverse psychotropic effects of THC, although this research is still emerging [8]. CBD has been used with a dosing in the range of 40 to 1280 mg/day orally [9].

Participants will receive 2 times/weekly research nurse phone calls in the first 2 weeks and out-patient clinic medical review visits at days 7, 14, 21 day 28, with outcome measures at these points.

Participants will be recruited from five sites of the Queensland Palliative Care Research Group (QPCRG). It is anticipated that this will be predominately an outpatient study.

Very few randomized controlled trials (RCTs) have been conducted using smoked cannabis (Campbell et al 2001) despite many anecdotal claims (Grinspoon and Bakalar 1997). One such study documented slight weight gain in HIV/AIDS subjects with no significant immunological sequelae (Abrams et al 2003). A recent brief trial of smoked cannabis (3.56% THC cigarettes 3 times daily) in HIV-associated neuropathy showed positive results on daily pain, hyperalgesia and 30% pain reduction (vs 15% in placebo) in 50 subjects over a treatment course of only 5 days (Abrams et al 2007) ( Table 1 ). This short clinical trial also demonstrated prominent adverse events associated with intoxication. In Canada, 21 subjects with chronic pain sequentially smoked single inhalations of 25 mg of cannabis (0, 2.5, 6.0, 9.5% THC) via a pipe three times a day for 5 days to assess effects on pain (Ware et al 2007) with results the authors termed “modest”: no changes were observed in acute neuropathic pain scores, and a very low number of subjects noted 30% pain relief at the end of the study ( Table 1 ). Even after political and legal considerations, it remains extremely unlikely that crude cannabis could ever be approved by the FDA as a prescription medicine as outlined in the FDA Botanical Guidance document (Food and Drug Administration 2004; Russo 2006b), due to a lack of rigorous standardization of the drug, an absence of Phase III clinical trials, and pulmonary sequelae (bronchial irritation and cough) associated with smoking (Tashkin 2005). Although cannabis vaporizers reduce potentially carcinogenic polyaromatic hydrocarbons, they have not been totally eliminated by this technology (Gieringer et al 2004; Hazekamp et al 2006).

Particular difficulties face the clinician managing intractable patients afflicted with cancer-associated pain, neuropathic pain, and central pain states (eg, pain associated with multiple sclerosis) that are often inadequately treated with available opiates, antidepressants and anticonvulsant drugs. Physicians are seeking new approaches to treatment of these conditions but many remain concerned about increasing governmental scrutiny of their prescribing practices (Fishman 2006), prescription drug abuse or diversion. The entry of cannabinoid medicines to the pharmacopoeia offers a novel approach to the issue of chronic pain management, offering new hope to many, but also stoking the flames of controversy among politicians and the public alike.

Cannabinoids and analgesic mechanisms

Results of a Phase III study (N = 177) comparing Sativex, THC-predominant extract and placebo in intractable pain due to cancer unresponsive to opiates (Johnson and Potts 2005) demonstrated that Sativex produced highly statistically significant improvements in analgesia ( Table 1 ), while the THC-predominant extract failed to produce statistical demarcation from placebo, suggesting the presence of CBD in the Sativex preparation was crucial to attain significant pain relief.

In 1988, the first cannabinoid receptor was identified (CB1) (Howlett et al 1988) and in 1993, a second was described (CB2) (Munro et al 1993). Both are 7-domain G-protein coupled receptors affecting cyclic-AMP, but CB1 is more pervasive throughout the body, with particular predilection to nociceptive areas of the central nervous system and spinal cord (Herkenham et al 1990; Hohmann et al 1999), as well as the peripheral nervous system (Fox et al 2001; Dogrul et al 2003) wherein synergy of activity between peripheral and central cannabinoid receptor function has been demonstrated (Dogrul et al 2003). CB2, while commonly reported as confined to lymphoid and immune tissues, is also proving to be an important mediator for suppressing both pain and inflammatory processes (Mackie 2006). Following the description of cannabinoid receptors, endogenous ligands for these were discovered: anandamide (arachidonylethanolamide, AEA) in 1992 in porcine brain (Devane et al 1992), and 2-arachidonylglycerol (2-AG) in 1995 in canine gut tissue (Mechoulam et al 1995) ( Figure 1 ). These endocannabinoids both act as retrograde messengers on G-protein coupled receptors, are synthesized on demand, and are especially active on glutamatergic and GABA-ergic synapses. Together, the cannabinoid receptors, their endogenous ligands (“endocannabinoids”) and metabolizing enzymes comprise the endocannabinoid system (ECS) (Di Marzo et al 1998), whose functions have been prosaically termed to be “relax, eat, sleep, forget and protect” (p. 528). The endocannabinoid system parallels and interacts at many points with the other major endogenous pain control systems: endorphin/enkephalin, vanilloid/transient receptor potential (TRPV), and inflammatory. Interestingly, our first knowledge of each pain system has derived from investigation of natural origin analgesic plants, respectively: cannabis (Cannabis sativa, C. indica) (THC, CBD and others), opium poppy (Papaver somniferun) (morphine, codeine), chile peppers (eg, Capsicum annuum, C. frutescens, C. chinense) (capsaicin) and willow bark (Salix spp.) (salicylic acid, leading to acetylsalicylic acid, or aspirin). Interestingly, THC along with AEA and 2-AG, are all partial agonists at the CB1 receptor. Notably, no endocannabinoid has ever been administered to humans, possibly due to issues of patentability and lack of commercial feasibility (Raphael Mechoulam, pers comm 2007). For an excellent comprehensive review of the endocannabinoid system, see Pacher et al (2006), while Walker and Huang have provided a key review of antinociceptive effects of cannabinoids in models of acute and persistent pain (Walker and Huang 2002).

Cannabis terpenoids also display numerous attributes that may be germane to pain treatment (McPartland and Russo 2001). Myrcene is analgesic, and such activity, in contrast to cannabinoids, is blocked by naloxone (Rao et al 1990), suggesting an opioid-like mechanism. It also blocks inflammation via PGE-2 (Lorenzetti et al 1991). The cannabis sesquiterpenoid β-caryophyllene shows increasing promise in this regard. It is anti-inflammatory comparable to phenylbutazone via PGE-1 (Basile et al 1988), but simultaneously acts as a gastric cytoprotective (Tambe et al 1996). The analgesic attributes of β-caryophyllene are increasingly credible with the discovery that it is a selective CB2 agonist (Gertsch et al 2007), with possibly broad clinical applications. α-Pinene also inhibits PGE-1 (Gil et al 1989), while linalool displays local anesthetic effects (Re et al 2000).