WO2020183456A1

WO2020183456A1 - Cannabinoid combinations for treating chronic pain in dialysis patients

Info

Publication number: WO2020183456A1
Application number: PCT/IL2020/050271
Authority: WO
Inventors: Tamir GEDO
Original assignee: Bol Pharma Ltd.
Priority date: 2019-03-10
Filing date: 2020-03-09
Publication date: 2020-09-17

Abstract

The present invention is directed to a cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD) and A9-tetrahydrocannabinol (THC), or enantiomers, diastereomers, or racemates thereof, for use in the treatment of chronic pain and associated symptoms in a subject suffering from end-stage renal disease (ESRD) and treated with dialysis, or for improving the efficacy and/or reducing adverse effects of at least one analgesic used for treating pain in a subject suffering from ESRD and treated with dialysis, wherein the CBD:THC weight ratio in the cannabinoid combination is about of 4:1 to about 10:1, preferably about 6:1.

Description

CANNABINOID COMBINATIONS FOR TREATING CHRONIC PAIN IN

DIALYSIS PATIENTS

FIELD OF THE INVENTION

[001] The present invention relates to a combination of Cannabidiol (CBD) and D⁹- Tetrahydrocannabinol (THC) for treating chronic pain and/or other symptoms associated with end-stage renal disease (ESRD) in dialysis patients.

BACKGROUND OF THE INVENTION

[002] Patients with end stage renal disease (ESRD) who are treated with chronic dialysis, are experiencing a significant decrease in the quality of life. Among the reasons for it are a decrease of function, side effects of the drugs, and the effect of the physiological and mental aspects of the kidney failure, most commonly symptoms are pain and depression. In a study conducted in Canada that included 205 patients with ESRD, about 50% of the patients suffered from chronic pain, and 82% of them rated the pain as intermediate to severe in level. Other studies indicated a similar frequency.

[003] The causes for pain in this population are variable, including pain arising from the kidney disease itself (such as in patients with autosomal dominant polycystic kidney disease), pain arising from background diseases (diabetic nephropathy, ulcers with a background of peripheral arterial occlusive disease), pain arising from complications of the ESRD (such as secondary hyperparathyroidism with bone factors, calciphylaxis) and pain arising from complications of the treatment with dialysis (e.g. fistula puncturing with thick needles, headaches or muscle contraction during the dialysis). Dialysis patients also suffer from bone or joint pain and also pain arising from muscle contraction. In the review of the 162 chronic hemodialysis patients, these pains were among the most common symptoms, with 50% of the patients reporting to have them. Muscle contractions have been reported in 43% of the patients.

[004] A study that evaluated pain in hemodialysis patients demonstrated that, in comparison to patients not reporting pain, patients who reported pain in an intermediate to severe degree had a significantly higher chance of suffering from depression (34% vs, 18%), sleep disorders (75% versus 53%) and a risk of stopping the dialysis treatment (46% versus 17%).

[005] In addition to pain, ESRD patients also suffer at a high frequency from symptoms including pruritus, sleep disorders, nausea, constipation, gastroparesis and suppression of the central nervous system. In a study that examined 591 ESRD patients, 54.3% reported nausea and 75.8% reported pruritus, while half of the patients reported an intermediate to severe degree of these symptoms. Pain and pruritus share common neural tracks, which may be the reason why that many ESRD patients suffer from neuropathic pain and pruritus at the same time.

[006] While drugs of the opioid type are effective pain killers, their side effects profile might cause an exacerbation of symptoms that are already present in dialysis patients, thereby preventing an improvement in the quality of life of the patients despite relieving the pain. In addition, prolonged use of opioids increases the risk for hormonal disorders, digestion problems, cognitive deterioration, hospitalization and even death due to overdose.

[007] There is also great importance to the characteristics of the drug, such as molecular weight, degree of solubility in water, the link to protein and the volume of dispersing in the body, which determine the degree of clearance during dialysis. In addition, the accumulation of metabolic waste with a biological impact due to inefficient clearing is also a problem for dialysis patients. For these reasons, morphine, which is a drug that is easily cleared in dialysis, is not an effective drug for dialysis patients, with the appearance of withdrawal effects during the treatment. Likewise, one of the morphine metabolic waste products is active and accumulates therefore necessitating dosage adjustments in chronic use. Other opioids also suffer from the disadvantages of the morphine, namely the slow clearance of the main compound and/or the metabolic waste products. Accordingly, it is generally recommended to avoid use of opioids in patients with ESRD.

[008] Nevertheless, there are opioid medications, for example methadone and fentanyl, that are relatively safe for use. They bind to the plasma proteins at a high rate, their clearing is mostly done through the intestine and their metabolic waste products are inactive. However, this methadone use can result in death due to toxicity, drug-drug interactions, or overdose, and fentanyl can result in serious and life-threatening complications involving hypoventilation. Additional drugs that are sometimes used are tramadol, which may accumulate with its metabolite leading, inter alia, to respiratory depression and reduced seizure threshold.

[009] As a result, many dialysis patients do not receive treatment for pain relief despite the reported high levels of pain. A systemic study in patients with ESRD has found that opioids are used for pain relief in patients with ESRD in between 5-36% of patients, but 17- 38% of patients treated with opioids s still suffer from intermediate to severe pain. [010] To summarize, the difficulties that accompany treatment with opioids in dialysis patients together with the multiple chronic symptoms, necessitate examining new treatment options in these patients to find a drug that may provide the following: treatment of both the pain and the accompanying symptoms such as decreased appetite, insomnia, and pruritus; a maximum safety profile; and minimal clearance during treatment with dialysis.

[011] The cannabis plant contains more than 421 chemical molecules, from which 66 have been identified as cannabinoid. The biological activity of these molecules is mediated mostly by two receptors, CB _IR and CB2_R. The first is common mostly in the brain, spine, intestinal nervous system, uterus, the prostate gland, the adrenal gland, liver and heart. The second receptor is linked more to the activity of the immune system and is found in white blood cells, the spleen, the tonsils and Thymus. Another family of receptors is the ion channel type that are operated via ionotropic cannabinoid Receptors and is found is peripheral sensory neurons.

[012] Of all the cannabinoid molecules identified, two molecules have been investigated more thoroughly, namely D⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). The main pharmacological effects of THC are pain relief, muscle relaxation, prevention of nausea and vomiting, appetite induction, and psychotropic effects; while for CBD they are pain relief, muscle relaxation, anti-seizure effect, anti-psychotic effect, anti-inflammatory effect, and effect of preserving neuronal structure and function.

[013] Medicinal cannabis is now being used for a number of indications, including relief of neuropathic and chronic pain (Wilsey 2013, Ronald 2009), contractions caused in multiple sclerosis, cachexia in cancer and AIDS patients, nausea and vomiting after chemotherapy, epilepsy and even glaucoma and schizophrenia. Medicinal cannabis has been documented to improve sleep (Lynch 2011) and preliminary studies indicate the involvement of endocannabinoids in the proper function and pathology of the skin and the option to treat pruritus in liver patients (Neff 2002) with endocannabinoids.

[014] As explained above with regard to opioids, water solubility and tissue distribution of a drug is relevant for evaluating its potential usefulness in treating dialysis patients. In general, drugs with a high water solubility are dialyzed to a greater extent than those with high lipid solubility. Highly lipid-soluble drugs tend to be distributed throughout tissues, and therefore only a small fraction of the drug is present in plasma and accessible for dialysis. Drugs with a high degree of protein binding tend to have a small plasma concentration of unbound drug available for dialysis. [015] Data from Huestis 2007, Garrett 1974, and Dean 2004 show that opioids have a much lower distribution volume and a much higher water solubility than that of cannabinoids; and % protein bonding also much lower for the opioids compared to the cannabinoids, except for the methadone and fentanyl, which are considered safe to use. These findings predict a high probability that the cannabinoids will not be cleared from the body during dialysis and therefore administration of cannabis to dialysis patients will not be accompanied by withdrawal effect.

[016] There is no evidence to suggest that cannabinoids have any adverse effect on kidney function in healthy individuals and patients with chronic kidney disease.

SUMMARY OF INVENTION

[017] In one aspect, the present invention provides a cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD) and D⁹-tetrahydrocannabinol (THC), or enantiomers, diastereomers, or racemates thereof, for use in the treatment of chronic pain and associated symptoms in a subject suffering from end-stage renal disease (ESRD) and treated with dialysis, wherein the CBD:THC weight ratio in the cannabinoid combination is about of 4:1 to about 10:1.

[018] In another aspect, the present invention provides a cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD) and A9-tetrahydrocannabinol (THC), or enantiomers, diastereomers, or racemates thereof, for use in improving the efficacy and/or for reducing adverse effects of at least one analgesic used for treating pain in a subject suffering from end-stage renal disease (ESRD) and treated with dialysis, wherein the CBD:THC weight ratio in the cannabinoid combination is about of 4:1 to about 10:1.

[019] In yet another aspect, the present invention provides a method for treating chronic pain and associated symptoms in a subject suffering from end-stage renal disease (ESRD) and treated with dialysis, the method comprising administering to a subject in need thereof a therapeutically effective amount of a cannabinoid combination comprising cannabidiol (CBD) and A9-tetrahydrocannabinol (THC), or enantiomers, diastereomers, or racemates thereof, wherein the CBD and A9-THC are at a weight ratio of from about 4:1 to about 10:1.

[020] In an additional aspect, the present invention provides a method for improving the efficacy and/or reducing adverse effects of at least one analgesic used for treating pain in a subject suffering from end-stage renal disease (ESRD) and treated with dialysis, the method comprising administering to the subject a therapeutically effective amount of a cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD) and D9- tetrahydrocannabinol (THC), or enantiomers, diastereomers, or racemates thereof, wherein the CBD:THC weight ratio in the cannabinoid combination is about of 4:1 to about 10:1.

DETAILED DESCRIPTION

[021] In the present application, the inventors tested combinations of cannabidiol (CBD) and D⁹-tetrahydrocannabinol (THC) at specific ratios, that are especially useful for treatment of chronic pain or other undesired symptoms in a subject suffering from end-stage renal disease (ESRD) and treated with dialysis.

[022] Therefore, in one aspect, the present invention provides a cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD) and D⁹-tetrahydrocannabinol (THC), or enantiomers, diastereomers, or racemates thereof, for use in the treatment of chronic pain and associated symptoms in a subject suffering from end-stage renal disease (ESRD) and treated with dialysis, wherein the CBD:THC weight ratio in the cannabinoid combination is about of 4:1 to about 10:1.

[023] The term "treating", or "treatment", as used herein refers to means of obtaining a desired physiological effect, such as pain relief, or improvement of other undesired symptoms such as quality of sleep, that are disturbed in the subject as a result of a medical condition or as a side effect of a medication. The effect may be partially or completely eliminating the symptom being treated.

[024] The term “cannabinoid combination” relates in the present application to a combination of the two cannabinoids, CBD and THC. The cannabinoid combination may be formulated as a single composition or as more than one composition. In other words, the CBD and THC may be comprised in a single composition containing CBD and THC at the desired ratio, or in at least two different compositions that may be combined to arrive at the desired CBD:THC ratio, each containing only CBD, only THC, or CBD and THC at a ratio different from the final desired ratio.

[025] Accordingly, in some embodiments, the cannabinoid combination is formulated as a sole pharmaceutical composition, optionally further comprising a pharmaceutically acceptable carrier.

[026] In some embodiments, the cannabinoid combination is formulated as a sole nutraceutical composition, optionally further comprising a nutraceutically acceptable carrier.

[027] In some embodiments, the cannabinoid combination is formulated as more than one pharmaceutical or nutraceutical composition. [028] The phrase "as the only cannabinoids" as used herein means that the only cannabinoids comprised in the cannabinoid combination are CBD and THC.

[029] In some embodiments, the cannabinoid combination of the invention is prepared from substantially pure preparations of CBD and/or THC.

[030] The term "substantially pure" means that the cannabinoid constitutes at least 95% of the weight of the preparation, and that no other active ingredient is present in the preparation in an amount detectable by HPLC.

[031] In some embodiments, the purity of the substantially pure CBD and/or THC preparations is at least 95%, 96%, at least 97%, at least 98%, or at least 99%.

[032] CBD (2-[6-isopropenyl-3-methylcyclohex-2-en-l-yl]-5-pentylbenzene-l,3-diol), has very low affinity for the cannabinoid CB i and CB2 receptors but is said to act as an indirect antagonist of these receptors. At the same time, it may potentiate the effects of D⁹- THC by increasing CBi receptor density or through another CBi receptor-related mechanism. CBD has two stereogenic centers, located at positions 3 and 4 of the cyclohexenyl ring, and may accordingly exist as an enantiomer, i.e., optical isomer, a racemate, i.e., an optically inactive mixture having equal amounts of two enantiomers, a diastereoisomer, or a mixture thereof. The present invention encompasses the use of all such enantiomers, isomers and mixtures thereof. CBD naturally exists as (2-[(1R, R)-6-isopropenyl-3-methylcyclohex-2-en- 1 -yl] -5-pentylbenzene- 1 ,3 -diol) .

[033] THC (6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-l-ol) is a partial agonist of the cannabinoid receptor CB i, located mainly in the central nervous system, and the CB2 receptor, mainly expressed in cells of the immune system. D⁹-THC has two stereogenic centers, located at positions 3 and 4 of the cyclohexenyl ring, and may accordingly exist as an enantiomer, i.e., an optical isomer, racemate, i.e., an optically inactive mixture having equal amounts of the two enantiomers, a diastereoisomer, or a mixture thereof. The present invention encompasses the use of all such enantiomers, isomers and mixtures thereof. D⁹-THC naturally exists as (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a- tetrahydro-6H-benzo[c]chromen-1-ol.

[034] For purposes of clarity, the terms CBD and THC as used throughout the description and the claims are intended to include enantiomer, diastereomer, or racemate thereof.

[035] In some embodiments, the CBD and/or THC are the naturally existing enantiomers, (2-[(1R, R)-6-isopropenyl-3 -methylcyclohex-2-en- 1 -yl] -5 -pentylbenzene- 1,3- diol) and (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-l- ol, respectively.

[036] Natural cannabinoids, including CBD and THC may be extracted from the cannabis plant using any suitable extraction or purification method known in the art, such as methods described, for example, in Gaoni and Mechoulam, J. Am. Chem. Soc. 93: 217-224 (1971), or by the method described below in the experimental section. A chemical signature may be made by a mass spectrometer so as to distinguish between a preparation made from an extract and a preparation made from the purified active ingredients.

[037] Alternatively, each of these cannabinoids may be synthesized following any one of the procedures disclosed in the literature. For example, CBD may be synthesized following any one of the procedures known in the art, e.g., by acid condensation of p-mentha-2,8-dien- l-ol with olivetol. Optically active forms of CBD or THC may be prepared using any one of the methods disclosed in the art, e.g., by resolution of the racemic form by recrystallization techniques; chiral synthesis; extraction with chiral solvents; or chromatographic separation using a chiral stationary phase. A non-limiting example of a method for obtaining optically active materials is transport across chiral membranes, i.e., a technique whereby a racemate is placed in contact with a thin membrane barrier, the concentration or pressure differential causes preferential transport across the membrane barrier, and separation occurs as a result of the non-racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through. Chiral chromatography, including simulated moving bed chromatography, can also be used. A wide variety of chiral stationary phases are commercially available.

[038] In some embodiments, the cannabinoid combination does not comprise terpenes.

[039] In some embodiments, the cannabinoid combination consists essentially of CBD and THC.

[040] The phrase“consists essentially of’ or“consisting essentially of’, as used herein with respect to the cannabinoid combination of the present invention, means that the CBD and THC are the only active agents in the cannabinoid combination. However, inactive agents such as those used in compositions and particularly in pharmaceutical compositions, including carriers, solvents, dispersion media, preservatives, antioxidants, coatings, and isotonic and absorption delaying agents, may be comprised in the cannabinoid combination of the invention.

[041] Each of the compositions mentioned above, which includes one or both of the CBD and THC, may be formulated for any suitable administration route as defined below, but is preferably formulated for oral, or sublingual administration, or for inhalation. In some specific embodiments, the pharmaceutical composition of the invention is administered by sublingual administration.

[042] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" as used herein interchangeably refers to any and all solvents, dispersion media, preservatives, antioxidants, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. According to the present invention, the pharmaceutically acceptable carrier may further comprise ingredients aimed at enhancing the activity of the active agents or modulating the bioavailability thereof.

[043] The term "acceptable" with respect to the pharmaceutically acceptable carrier denotes a carrier, excipient, or non-active ingredient that does not produce an adverse, allergic, or other untoward reaction when administered to a mammal or human as appropriate. For human administration, compositions should meet sterility, pyrogenicity, and general safety and purity standards as required by, e.g., the U.S. FDA or the European Medicines Agency (EMA).

[044] The pharmaceutical compositions disclosed herein may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 19^th Ed., 1995. The compositions can be prepared, e.g., by uniformly and intimately bringing the active agents into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation. The compositions may be in the form of a liquid (e.g., solution, emulsion, or suspension), gel, cream, solid, semisolid, film, lyophilisate, or aerosol, and may further include pharmaceutically acceptable fillers, carriers, diluents or adjuvants, and other inert ingredients and excipients. In one embodiment, the pharmaceutical composition of the present invention is formulated as nanoparticles.

[045] The pharmaceutical compositions of the present invention may be formulated for any suitable route of administration, e.g., for oral, buccal, sublingual, or parenteral, e.g., intravenous, intraarterial, intramuscular, intraperitoneal, intrathecal, intrapleural, intratracheal, subcutaneous, or topical, administration, as well as for inhalation, but is preferably formulated for oral or sublingual administration, or for inhalation.

[046] The pharmaceutical compositions of the invention, when formulated for oral administration, may be in any suitable form, e.g., tablets, troches, lozenges, aqueous, or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. In certain embodiments, the tablets are in the form of matrix tablets in which the release of a soluble active is controlled by having the active agent diffuse through a gel formed after the swelling of a hydrophilic polymer brought into contact with dissolving liquid (in vitro) or gastro-intestinal fluid (in vivo). Many polymers have been described as capable of forming such gel, e.g., derivatives of cellulose, in particular the cellulose ethers such as hydroxypropyl cellulose, hydroxymethyl cellulose, methylcellulose or methyl hydroxypropyl cellulose, and among the different commercial grades of these ethers are those showing fairly high viscosity. In other embodiments, the tablets are formulated as bi- or multi-layer tablets, made up of two or more distinct layers of granulation compressed together with the individual layers lying one on top of another, with each separate layer containing a different active agent. Bilayer tablets have the appearance of a sandwich since the edge of each layer or zone is exposed.

[047] Pharmaceutical compositions for oral administration might be formulated so as to inhibit the release of one or both of the active agents in the stomach, i.e., delay the release of one or both of the active agents until at least a portion of the dosage form has traversed the stomach, in order to avoid the acidity of the gastric contents from hydrolyzing the active agent. Particular such compositions are those wherein the active agent is coated by a pH- dependent enteric-coating polymer. Examples of pH-dependent enteric-coating polymer include, without being limited to, Eudragit^® S (poly(methacrylicacid, methylmethacrylate), 1:2), Eudragit^® L 55 (poly (methacrylicacid, ethylacrylate), 1:1), Kollicoat^® (poly(methacrylicacid, ethylacrylate), 1:1), hydroxypropyl methylcellulose phthalate (HPMCP), alginates, carboxymethylcellulose, and combinations thereof. The pH-dependent enteric-coating polymer may be present in the composition in an amount from about 10% to about 95% by weight of the entire composition.

[048] In certain embodiments, the invention provides pharmaceutical compositions for oral administration, which is solid and may be in the form of granulate, granules, grains, beads or pellets, mixed and filled into capsules or sachets, or compressed to tablets by conventional methods. In some particular embodiments, the pharmaceutical composition is in the form of a bi- or multilayer tablet, in which each one of the layers comprise one of the active agents, and the layers are optionally separated by an intermediate, inactive layer, e.g., a layer comprising one or more disintegrants.

[049] Another contemplated formulation is depot systems, based on biodegradable polymers. As the polymer degrades, the active agent(s) is slowly released. The most common class of biodegradable polymers is the hydrolytically labile polyesters prepared from lactic acid, glycolic acid, or combinations of these two molecules. Polymers prepared from these individual monomers include poly (D,L-lactide) (PLA), poly (glycolide) (PGA), and the copolymer poly (D,L-lactide-co-glycolide) (PLG).

[050] Pharmaceutical compositions for oral administration may be prepared according to any method known to the art and may further comprise one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active agents in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets. These excipients may be, e.g., inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents, e.g., com starch or alginic acid; binding agents, e.g., starch, gelatin or acacia; and lubricating agents, e.g., magnesium stearate, stearic acid, or talc. The tablets may be either uncoated or coated utilizing known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated using the techniques described in the US Patent Nos. 4,256,108, 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for control release. The pharmaceutical composition of the invention may also be in the form of oil-in-water emulsion.

[051] Useful dosage forms of the pharmaceutical compositions include orally disintegrating systems including, but not limited to, solid, semi-solid and liquid systems including disintegrating or dissolving tablets, soft or hard capsules, gels, fast dispersing dosage forms, controlled dispersing dosage forms, caplets, films, wafers, ovules, granules, buccal/mucoadhesive patches, powders, freeze dried (lyophilized) wafers, chewable tablets which disintegrate with saliva in the buccal/mouth cavity and combinations thereof. Useful films include, but are not limited to, single layer stand-alone films and dry multiple layer stand-alone films.

[052] The pharmaceutical composition of the invention may comprise one or more pharmaceutically acceptable excipients. For example, a tablet may comprise at least one filler, e.g., lactose, ethylcellulose, microcrystalline cellulose, silicified microcrystalline cellulose; at least one disintegrant, e.g., cross-linked polyvinylpyrrolidinone; at least one binder, e.g., polyvinylpyridone, hydroxypropylmethyl cellulose; at least one surfactant, e.g., sodium laurylsulfate; at least one glidant, e.g., colloidal silicon dioxide; and at least one lubricant, e.g., magnesium stearate. [053] The pharmaceutical composition of the invention may be in the form of a sterile injectable aqueous or oleagenous suspension, which may be formulated according to the known art using suitable dispersing, wetting or suspending agents. The sterile injectable preparation may also be an injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Acceptable vehicles and solvents that may be employed include, without limiting, water, Ringer's solution, polyethylene glycol (PEG), 2- hydroxypropyl-P-cyclodextrin (HPCD), a surfactant such as Tween-80, and isotonic sodium chloride solution.

[054] Pharmaceutical compositions according to the invention, when formulated for inhalation, may be in any suitable form, e.g., liquid or fine powder, and may be administered utilizing any suitable device known in the art, such as pressurized metered dose inhalers, liquid nebulizers, dry powder inhalers, sprayers, thermal vaporizers, electrohydrodynamic aerosolizers, and the like.

[055] The pharmaceutical compositions of the invention may be formulated for controlled release of one or more of the active agents. Such compositions may be formulated as controlled-release matrix, e.g., as controlled -release matrix tablets in which the release of a soluble active agent is controlled by having the active agent diffuse through a gel formed after the swelling of a hydrophilic polymer brought into contact with dissolving liquid (in vitro ) or gastro-intestinal fluid (in vivo). Many polymers have been described as capable of forming such gel, e.g., derivatives of cellulose, in particular the cellulose ethers such as hydroxypropyl cellulose, hydroxymethyl cellulose, methylcellulose or methyl hydroxypropyl cellulose, and among the different commercial grades of these ethers are those showing fairly high viscosity. In other configurations, the compositions comprise the active agent formulated for controlled release in microencapsulated dosage form, in which small droplets of the active agent are surrounded by a coating or a membrane to form particles in the range of a few micrometers to a few millimeters.

[056] CBD and THC are insoluble in water but soluble in organic solvents, such as oil. Accordingly, they may be formulated for use in the described methods through use of any organic solvent known to the pharmaceutical arts, including, but not limited to edible oils. When formulated for oral administration, any edible oil can be used in the cannabinoid formulation, including olive oil.

[057] The nutraceutical composition may be formulated as a tablet, capsule, pill and powder, or as a liquid such as syrup, or elixir, drink or beverage, and may be prepared by conventional techniques known in the art. Particular such nutraceutical compositions are formulated for oral, buccal or sublingual administration, or for inhalation.

[058] In some embodiments, the CBD:THC weight ratio is about 5:1 to about 10:1, about 6:1 to about 10:1, about 4:1 to about 8:1, about 5:1 to about 8:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1 or about 10:1. In some embodiments, the CBD:THC weight ratio is about 6:1.

[059] In some embodiments, the CBD is formulated for administration at a daily dose of about 15 mg to about 150 mg, about 15 mg to about 135 mg, about 15 mg to about 90 mg, about 15 mg to about 45 mg, about 30 mg to about 90 mg, about 60 mg to about 90 mg, about 15 mg to about 60 mg, about 15 mg to about 30 mg, about 30 mg to about 60 mg, about 30 mg to about 150 mg; about 30 mg to about 135 mg; about 45 mg to about 135 mg, about 45 mg to about 90 mg, about 45 mg to about 60 mg, about 60 mg to about 150 mg, about 60 mg to about 135 mg, about 15 mg, about 30 mg, about 45 mg, about 60 mg, about 90 mg, about 135 mg, or about 150 mg.

[060] In some embodiments, the THC is formulated for administration at a daily dose of about 2.5 mg to about 25 mg, about 2.5 mg to about 22.5 mg, about 2.5 mg to about 15 mg, about 5 mg to about 15 mg, about 7.5 mg to about 15 mg, about 10 mg to about 15 mg, about

2.5 mg to about 10 mg, about 2.5 mg to about 7.5 mg, about 2.5 mg to about 5 mg, about 5 mg to about 10 mg, about 5 mg to about 25 mg, about 5 mg to about 22.5 mg, about 7.5 mg to about 25 mg, about 7.5 mg to about 22.5 mg, about 10 mg to about 25 mg, about 10 mg to about 22.5 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about

22.5 mg, or about 25 mg.

[061] The cannabinoid combination is formulated for administrations at the desired frequency, e.g. once, twice, or three times daily, or once every two or three days. In some embodiments, the cannabinoid combination is formulated for administration once, twice, or three times a day. In some embodiments, the cannabinoid combination is formulated for administration three times a day.

[062] In some embodiments, the cannabinoid combination is formulated for administration sublingually, orally, or by inhalation.

[063] When the CBD and the THC are not comprised in the same composition, the ratio of CBD:THC is calculated based on the daily amount of each cannabinoid.

[064] In some embodiments, the CBD and the THC are comprised in separate compositions and are administered concomitantly or sequentially at any order. [065] In some embodiments, the CBD and the THC are comprised in separate compositions and are independently administered sublingually, orally, or by inhalation.

[066] In some embodiments, the CBD and the THC are comprised in separate compositions and are independently administered once, twice, or three times a day.

[067] The subject intended to be treated according to the invention is suffering from end- stage renal disease (ESRD, also called Stage 5 chronic kidney disease, or end-stage kidney disease, or kidney/renal failure), and is treated with dialysis as a kidney replacement therapy. The subject may be suffering from various symptoms, including chronic pain, depression, decrease in quality of life, decrease in function, sleep disorders, pruritus, nausea, constipation, loss of appetite, restless leg syndrome (RLS), gastroparesis, vomiting, anxiety, fatigue, anemia, dyspnea, edema, congestive heart failure, arrythmia, uremia, electrolyte imbalance, neurological complications such as altered mental status (stroke, cognitive impairment, dementia, encephalopathy), peripheral neuropathy, autonomic neuropathy, and myopathy, that may arise from the kidney disease itself, from background diseases, from complications of the kidney disease, from complication of the dialysis, or from side effects of drugs administered for treating any of the conditions or symptoms mentioned above.

[068] In some embodiments, the subject suffers from at least one of autosomal dominant polycystic kidney disease; a background disease such as diabetic nephropathy or ulcers with a background of peripheral arterial occlusive disease; and a complication of the kidney disease, such as secondary hyperparathyroidism with bone factors or calciphylaxis. In some embodiments, the subject suffers from complication of the dialysis, such as a fistula puncturing with thick needles, a headache, muscle contraction, bone pain, or joint pain. In some embodiments, the subject suffers from side effects of drugs administered for treating any of the conditions or symptoms mentioned above. It is appreciated that the subject may suffer from more than one condition in more than one of the categories mentioned above.

[069] Accordingly, in some embodiments, the subject is suffering from at least one symptom, or disease parameter, selected from chronic pain, depression, decrease in quality of life, decrease in function, a sleep disorder, pruritus, nausea, constipation, loss of appetite, restless leg syndrome (RLS), gastroparesis, vomiting, anxiety, fatigue, anemia, dyspnea, edema, congestive heart failure, arrythmia, uremia, electrolyte imbalance, neurological complications such as altered mental status, peripheral neuropathy, autonomic neuropathy, and myopathy. [070] The term“chronic pain” relates to pain that lasts for a long time. In some embodiments, the chronic pain lasts for at least a month. In some embodiments, the chronic pain lasts for at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months.

[071] In some embodiments, the chronic pain is associated with at least one of a kidney disease, a background disease, a complications of the kidney disease, a complication of the dialysis, or a side effect of a drug administered to treat any of the above diseases or complications, or any symptoms associated with ESRD.

[072] In some embodiments, the chronic pain is neuropathic pain, bone pain, joint pain, and/or muscle pain.

[073] The term“associated symptoms” relates to any additional symptoms beside pain that are associated with the diseases and conditions mentioned above, or to side effects of the drug as mentioned above, including depression, decrease in quality of life, decrease in function, sleep disorders, pruritus, nausea, constipation, loss of appetite, restless leg syndrome (RLS), gastroparesis, vomiting, anxiety, fatigue, anemia, dyspnea, edema, congestive heart failure, arrythmia, uremia, electrolyte imbalance, neurological complications such as altered mental status, peripheral neuropathy, autonomic neuropathy, and myopathy.

[074] The term“dialysis” relates to any type of renal replacement therapy, including hemodialysis, peritoneal dialysis, hemofiltration, or hemodiafiltration.

[075] In some embodiments, the dialysis is hemodialysis or peritoneal dialysis.

[076] Dialysis may be used as a temporary measure in either acute kidney injury or in those awaiting kidney transplant, and as a permanent measure in those for whom a transplant is not indicated or not possible. For patients with ESRD, dialysis is chronic, or long term.

[077] Evaluating the severity, or intensity, of the chronic pain or of the associated symptoms may be carried out by any suitable method, including, but not limited to: 12-Item Short Form Survey (SF12), Brief pain Inventory (BPI), Chronic Pain Grade Questionnaire (CPG), Generalized Anxiety Disorder scale (GAD-7), Insomnia Severity Index (ISI, Bastien CH, Vallieres A, Morin CM., 2001, Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med. 4:297-307), Mankoski Pain Scale, McGill Pain Questionnaire, Numerical Pain Rating Scale (NPRS), Oswestry Disability Index, pain and cannabis administration log or the patient, Patient global impression of change (PGIC), Pittsburg Sleep Quality Index (PSQI), Quality of Life Questionnaire for Dialysis Patients (KDQOL-SF), RLS questionnaire, Roland Morris Disability Questionnaire, Simplified Nutritional Appetite Questionnaire (SNAQ), side effects questionnaire, Symptom Burden Questionnaire Adjusted for Dialysis Patients (ESAS), and Visual Analog scale (VAS) for pain severity.

[078] The methods for evaluating the severity of the chronic pain or the symptoms associated with ESRD demonstrated in the present application are the following: Generalized Anxiety Disorder scale (GAD-7), side effects questionnaire, Brief pain Inventory (BPI), Quality of Life Questionnaire for Dialysis Patients (KDQOL-SF), Symptom Burden Questionnaire Adjusted for Dialysis Patients (ESAS), Simplified Nutritional Appetite Questionnaire (SNAQ), RLS questionnaire, and Visual Analog scale (VAS) for pain severity (Haefeli and Elfering, 2006).

[079] Accordingly, in some embodiments, the treatment with the cannabinoid combination provides an improvement in at least one disease parameter selected from pain, depression, anxiety fatigue, dyspnea, numbness in extremity, dizziness, confusion, memory problems, euphoria, restlessness, somnolence, vomiting, abdominal pain, diarrhea, tachycardia, chest pain, itching, dry mouth, respiratory problems, recurrent infections, quality of life, quality of sleep, pruritus, nausea, constipation, appetite, and RLS.

[080] In some embodiments the improvement in the at least one disease parameter is measured by at least one method selected from Generalized Anxiety Disorder scale (GAD-7), side effects questionnaire, Brief pain Inventory (BPI), Quality of Life Questionnaire for Dialysis Patients (KDQOL-SF), Symptom Burden Questionnaire Adjusted for Dialysis Patients (ESAS), Simplified Nutritional Appetite Questionnaire (SNAQ), RLS questionnaire, and Visual Analog scale (VAS) for pain severity.

[081] The improvement is measured by comparing the scores in the relevant methods, which reflect the status of the parameters measured in the subject during treatment. The scores obtained following treatment with the cannabinoid combination of the invention are compared to a reference such as the respective scores (by the same methods) prior to treatment with the cannabinoid combination, or scores of a control case in the same situation but not receiving the cannabinoid combination.

[082] Accordingly, in some embodiments, the improvement in at least one disease parameter is relative to the status, or the score, of the at least one disease parameter prior to treatment by the cannabinoid combination.

[083] In some embodiments, the improvement is by at least 10%, 20%, 20%, 30%, 40%, 50%, 60%, or 70%. [084] In some embodiments, the subject is a male subject. In some embodiments, the subject is a female subject. In some embodiments, the subject is an adult. In some embodiments, the subject is over 30 years old prior to treatment. In some embodiments, the subject is over 50, over 60, or over 70 years old prior to treatment. In some embodiments, the subject smoked cigarettes prior to treatment. In some embodiments, the subject suffers from diabetes. In some embodiments, the subject had hypertension prior to the treatment according to the invention. In some embodiments, the subject suffers from a vascular disease. In some embodiments, the subject suffers from a glomerular disease. In some embodiments, the subject suffers from a cystic kidney disease. In some embodiments, the subject suffers from a tubulointerstitial disease. In some embodiments, the subject suffered from urinary tract obstruction or dysfunction prior to the treatment. In some embodiments, the subject has a congenital defect of the kidney or bladder. In some embodiments, the subject suffered an unrecovered acute kidney injury.

[085] In some embodiments, the subject receives at least one analgesic in addition to the cannabinoid combination.

[086] In some embodiments, the at least one analgesic is an opioid, such as morphine, methadone, fentanyl, or tramadol. In some embodiments, the analgesic is an acetaminophen. In some embodiments, the analgesic is buprenorphine, tapentadol, oxycodone, hydrocodone, oxymorphone, or hydromorphne.

[087] In some embodiments, the subject has been non-responsive to treatment with an analgesic. In some embodiments, the subject has been non-responsive to treatment with an analgesic for at least one month during a time period before the treatment according to the invention. In some embodiments, the subject has been non-responsive to treatment with the same analgesic used together with the cannabinoid combination according to the invention, prior to the treatment with the cannabinoid combination. In some embodiments, the subject has been non-responsive to treatment with the analgesic used together with the cannabinoid combination according to the invention for at least one month during a time period prior to the treatment with the cannabinoid combination.

[088] In some embodiments, the subject is not able to receive an opioid, e.g. because of an adverse reaction to opioids, which reduce the quality of life of the subject.

[089] In some embodiments, the subject suffers a level of pain of at least 5, as measured by the VAS questionnaire (VAS Score >5) before treatment. [090] In some embodiments, one or more of the at least one analgesic is administered according to the invention at a daily dose lower than the daily dose recommended by the manufacturer or previously taken by the subject to achieve the same therapeutic effect.

[091] In some embodiments, the daily dose of one or more of the at least one analgesic is at least 10%, 20%, 30%, 40%, 50%, 60%, 70% lower than lowest daily dose recommended by the Manufacturer.

[092] In some embodiments, the daily dose of one or more of the at least one analgesic is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70% lower than daily dose recommended for the subject.

[093] In some embodiments, the daily dose of one or more of the at least one analgesic is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70% lower than the daily dose which the subject was taking to achieve the same therapeutic effect before commencement of treatment with the cannabinoid combination.

[094] In some embodiments, the daily dose of the opioid analgesic is at least 5 morphine milligram equivalents (MME), 10 MME, 20 MME ,30 MME, 40 MME, 50 MME, 60 MME, 70 MME, 80 MME or 90 MME lower than daily dose recommended for the subject.

[095] In some embodiments, the daily dose of the opioid analgesic is at least 5 morphine milligram equivalents (MME), 10 MME, 20 MME ,30 MME, 40 MME, 50 MME, 60 MME, 70 MME, 80 MME or 90 MME lower than the daily dose which the subject was taking to achieve the same therapeutic effect before commencement of treatment with the cannabinoid combination.

[096] In some embodiments, one or more of the at least one analgesic is administered at a sub-therapeutic dose.

[097] The term "sub-therapeutic dose" as used herein means less than the therapeutic dose of the drug that is needed to produce a therapeutic effect when the drug is used to treat the disease or condition it is administered for.

[098] In some embodiments, treatment with the cannabinoid combination together with one or more of the at least one analgesic according to the invention results in fewer adverse effects compared to treatment with the at least one analgesic without the cannabinoid combination.

[099] In some embodiments, treatment with the cannabinoid combination together with one or more of the at least one analgesic according to the invention results in the elimination, reduced frequency, or reduced severity of at least one adverse effect selected from pain, depression, pruritus, nausea, constipation, decreased appetite up to loss of appetite, RLS, dizziness, somnolence, confusional state, mood altered, anxiety, nervousness, euphoric mood, sleep disorders, headache, trembling, vomiting, dry mouth, diarrhea, abdominal pain, dyspepsia, flatulence, hyperhidrosis, dry mouth, fatigue, gastrointestinal irritation, postural hypotension, dermal reactions (e.g. rash, urticaria purpura, angioedema, exfoliative and bullous dermatoses); dyspepsia, flatulence, anorexia transaminases increased, thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia, haemolytic anaemia, non specific allergic reactions and anaphylaxis, respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnea, insomnia, confusion, hallucinations, disorientation, paraesthesia, tremor, weakness, drowsiness, optic neuritis, tinnitus, vertigo, oedema, hypertension, palpitation and cardiac failure, arterial thrombotic events (for example myocardial infarction or stroke), vasculitis, peptic ulcers, perforation or GI bleeding, ulcerative stomatitis, rectal bleeding, exacerbation of colitis and Crohn's disease, gastritis, pancreatitis, abnormal liver function, hepatitis and jaundice, haematemesis, melaena, nephrotoxicity, asthenia, chills, vertigo, hot flush, altered mood and personality change, decreased activity, psychomotor hyperactivity, hiccups and dysuria, compared to treatment with the analgesic without the cannabinoid combination.

[0100] In some embodiments, the severity of at least one adverse effect during treatment with cannabinoid combination together with an analgesic according to the invention is lower than the severity of that adverse effect during treatment with the analgesic without the cannabinoid combination.

[0101] The term“severity” relates to the intensity of the adverse effect, and is classified as mild, moderate, or severe.

[0102] In some embodiments, the subject was being treated with the analgesic prior to commencement of treatment with the cannabinoid combination. In some embodiments, the subject was treated with a different analgesic prior to treating with the cannabinoid combination of the invention and the analgesic.

[0103] The cannabinoid combination may be administered to the subject concomitantly or sequentially at any order with the analgesic. In some embodiments, the cannabinoid combination is administered to the subject prior to treatment with the analgesic.

[0104] In another aspect, the present invention provides a cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD) and D⁹-tetrahydrocannabinol (THC), or enantiomers, diastereomers, or racemates thereof, for use in improving the efficacy and/or for reducing adverse effects of at least one analgesic used for treating pain in a subject suffering from end-stage renal disease (ESRD) and treated with dialysis, wherein the CBD:THC weight ratio in the cannabinoid combination is about of 4:1 to about 10:1.

[0105] In some embodiments, the CBD:THC weight ratio is about 6:1.

[0106] In a further aspect, the present invention provides a method for treating chronic pain and associated symptoms in a subject suffering from end-stage renal disease (ESRD) and treated with dialysis, the method comprising administering to a subject in need thereof a therapeutically effective amount of a cannabinoid combination comprising cannabidiol (CBD) and D⁹-tetrahydrocannabinol (THC), or enantiomers, diastereomers, or racemates thereof, wherein the CBD and D⁹-THC are at a weight ratio of from about 4:1 to about 10:1.

[0107] The term "therapeutically effective amount" as used herein means an amount of the cannabinoid combination that will elicit the biological or medical response of a tissue, system, animal or human that is being sought. The amount must be effective to achieve the desired therapeutic effect as described above, depending inter alia on the type and severity of the condition to be treated and the treatment regime. The effective amount is typically determined in appropriately designed clinical trials (dose range studies) and the person skilled in the art will know how to properly conduct such trials to determine the effective amount. As generally known, an effective amount depends on a variety of factors including the affinity of the ligand to the receptor, its distribution profile within the body, a variety of pharmacological parameters such as half-life in the body, on undesired side effects, if any, and on factors such as age and gender, etc.

[0108] In yet a further aspect, the present invention provides a method for improving the efficacy and/or reducing adverse effects of at least one analgesic used for treating pain in a subject suffering from end-stage renal disease (ESRD) and treated with dialysis, the method comprising administering to the subject a therapeutically effective amount of a cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD) and D⁹- tetrahydrocannabinol (THC), or enantiomers, diastereomers, or racemates thereof, wherein the CBD:THC weight ratio in the cannabinoid combination is about of 4:1 to about 10:1.

[0109] It is conceivable that the cannabinoid combination of the invention, including CBD, and D⁹-THC will be provided as a kit. Such a kit includes two compositions, each comprising one of the two cannabinoids. The kit may further include the analgesic.

[0110] Unless otherwise indicated, all numbers expressing, e.g., weight ratios or doses of the two cannabinoids defined above, used in this specification are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification are approximations that may vary by up to plus or minus 10% depending upon the desired properties to be obtained by the present invention.

[0111] The invention will now be illustrated by the following non-limiting Examples.

EXAMPLES

Example 1: The effect of a combination of CBD and THC on dialysis patients

Participants

[0112] The participants are 30-80 years old dialysis patients who have been treated with opioids and do not feel a relief in pain, or that as a result of the treatment, symptoms that are related to dialysis have appeared or exacerbated and the patients are experiencing a decrease in the quality of life. This group also includes patients who have been treated for pain in a second line of treatment according to the definitions of the global health organization and the level of the pain is high or equal to 5 (Visual Analog scale (VAS) Score >5) or patients who cannot receive an opioid treatment or who are responding with significant side effects to such a treatment. Patients generally continue receiving the same analgesic, provided that the opioids dose does not exceed 40 morphine milligram equivalents (MME) per 24 hours prior to the trial.

[0113] Based on previous studies to find out the change of one unit in the Numerical Pain Rating Scale (NPRS) index (pain rating) and change in the standard deviation of 1.7 and in the degree of relation of 80% and the significance level of (( 0.05 >p, in a bilateral hypothesis, a sample size of 60 men and women is required, however, since it is taken into account that according to previous studies, the drop-out rate is expected to be about 10%, we adjust for a sample size of 60 recruited patients. Calculating the sample size is done via the WINPEPI software (version 11.65).

Study design

[0114] The study includes 3 arms, each arm includes 2 treatment sequences of 2 months each with a 2 week wash-out period between them. Each treatment period begins with a titration period of 2 weeks, for personal adjustment of the dosage, which is followed by 6 weeks of the full treatment. At the end of the trial, there is a follow up period of 4 weeks without treatment.

[0115] In each arm, every participant receives in the two treatment sequences two of the three preparations in the study: 1. full cannabis extract from a plant, 2. purified THC and CBD, 3. a placebo preparation. In both preparations 1 and 2, that contain an active substance there is an identical concentration of THC and CBD and in a ratio of 6: 1 CBD:THC.

[0116] The patients begin the titration phase with 3 drops (0.1 ml total) before sleep and the dose is increased gradually to 6 drops (3 drops in the morning and 3 drops in the evening) and on the first weekend to 3 drops 3 times per day in the maximum daily dosage of 7.5 mg THC and 45 mg of CBD. If there are no side effects, the dose is increased to 4 drops 3 times per day, then to 5 drops 3 times per day, and on the second weekend, the participant receives 6 drops 3 times per day (30 mg of CBD and 5 mg of THC per dose; or 90 mg CBD and 15 mg THC per day). In unusual events, if there is no sufficient reaction, the dose can be increased to 9 drops 1-3 times per day (up to a final dose of 135 mg CBD and 22.5 mg THC per day). These amounts have been reported as effective in pain relief (Noyes 1975, Eisenberg 2014).

[0117] The placebo sublingual drops formulation is very similar to the Investigational Medicinal Product (IMP), only without the CBD and THC. Here also, the dosage volume is 0.034 ml of placebo (olive oil) and is achieved by administering the appropriate number of 0.034 ml drops. The placebo is administered after meals as well to maintain blinding. Both the IMP and the placebo have identical color, taste and smell to maintain blinding.

Preparation of purified cannabinoids

[0118] Cannabis sativa flowers are dried and ground. The ground plant material contains CBD, and THC in their acidic forms - CBDa and THCa. Decarboxylation process performed at 140°C turned the CBDa and THCa to CBD and THC, while releasing CO2 gas. CBD and THC are extracted from the decarboxylated material via supercritical CO2 extraction. The extract is dissolved in ethanol following winterization step at -20°C for 48 hours. The ethanolic winterized extract is filtered to remove waxy constitutes, and the ethanol is evaporated.

[0119] For CBD (cannabidiol, CAS Number: 13956-29-1) preparation, the dried extract is dissolved in pentane under heat to achieve super saturation and cooled to room temperature. Crystallization takes place in two stages: first stage: -20°C, second stage: 4°c. After crystallization, the CBD is dried and milled, and stored in air-tight containers, protected from air and light at room temperature.

[0120] For THC (CAS Number: 1972-08-3) preparation, the dried extract is dissolved in cyclohexane and separated in a normal phase column with cyclohexane/ethyl acetate. The clean fractions are dried and dissolved in methanol: water 70:30 for reverse phase chromatography. The reverse phase clean fractions are dried and washed twice with ethanol. The ethanol solution is evaporated to receive neat THC. THC is stored at 4°C under nitrogen in glass containers, protected from light.

[0121] The cannabinoids are >95% pure.

Cannabinoids in oil

[0122] Cannabinoids are added to olive oil in a beaker to concentration of 150 mg/ml CBD and 25 mg/ml THC. The beaker is closed with a glass cover, and the mixture is stirred with magnetic stirrer for 60 minutes. The solution is then tested for cannabinoids concentration via HPLC. Each drop has a volume of 0.034 ml and contains 5 mg CBD and 0.833 mg THC.

Parameters tested

[0123] The effect of the treatment with cannabis oil on pain as well as symptoms of the kidney disease or side effects from opioids treatment, including pruritus, quality of sleep, anxiety, appetite, and RLS (restless leg syndrome) is examined throughout the study.

[0124] Throughout the study, various tests are administered and parameters are measured, including a complete physical examination (including height and weight measurements), vital signs (including temperature, peripheral arterial blood pressure, heart rate, and respiratory rate), electrocardiogram (ECG). urinalysis, and laboratory assessments including complete blood count (CBC), C-reactive protein (CRP), Glucose, erythrocyte sedimentation rate (ESR), and HbAlc level.

[0125] In addition, the following questionnaires are administered: demographic questionnaire, medical history, details about the kidney disease and dialysis, list of drugs, General Anxiety Disorder scale (GAD-7) to assess the severity of anxiety, side effects questionnaire for assessing adverse effects, Brief pain Inventory (BPI) for assessing severity of pain and effect on function, Quality of Life Questionnaire for Dialysis Patients (KDQOL- SF), Symptom Burden Questionnaire Adjusted for Dialysis Patients (Modified Edmonton symptom assessment system (ESAS)), Simplified Nutritional Appetite Questionnaire (SNAQ), pain and cannabis administration log or the patient, RLS questionnaire (International Restless Legs Syndrome Study Group Rating Scale).

[0126] The quality of sleep is monitored by a sleep questionnaire (implemented in the Quality of Life Questionnaire) and by using an actigraphy watch. The assessment is made one week prior to the start of the treatment, one week prior to the end of the first treatment chapter, and one week prior to the end of the second treatment chapter. Parallel to using the actigraphy watch, the patient is asked to fill out a sleep log in which they will document the time of going to bed and the time of waking up. Assessment methods in more detail

[0127] Brief Pain Inventory (BPI): is utilized to measure both the intensity of pain (sensory dimension - severity subscore) and interference of pain in the patient’s life (reactive dimension - interference subscore) (Cleeland and Ryan, 1994). It assesses patient’s quality of pain, treatment-related pain relief, and patient’s perception of the cause of pain. The evaluation is carried out through a number of different scales. Patients are presented with line drawings of the front and back of a human body and are asked to mark the location of their pain. Patients are asked to list the treatments or medications that they are using and how much relief they have provided during the past 24 hours. In addition, patients fill out 11 different numeric rating scales regarding pain intensity and the effect of the pain on their ability to function during various activities of daily living. BPI is a validated tool for monitoring the effect of pain, or treatment of pain, or both, in terms of a patient’s functional ability or disability over time.

[0128] Visual Analog scale (VAS) for pain severity : VAS consists of a 100mm line with the endpoints defining extreme limits as‘no pain at all’ and‘pain as bad as it could be’ (Haefeli and Elfering, 2006, Eur Spine J. 15(Suppl 1): S17-S24). Patients are asked to evaluate the severity of their pain and mark their evaluation on the line between the two endpoints. Individual VAS score is the numeric value, which corresponds to the individual evaluation of the severity of pain.

[0129] Generalized Anxiety Disorder (GAD-7) questionnaire is a seven-item, self-report anxiety questionnaire designed to assess the patient's health status during the previous 2 weeks. GAD-7 total score for the seven items ranges from 0 to 21. Interpretation. Scores of 5, 10, and 15 represent cut-points for mild, moderate, and severe anxiety, respectively. When used as a screening tool, further evaluation is recommended when the score is 10 or greater (Spitzer RL, Kroenke K, Williams JBW, Lowe B. A brief measure for assessing generalized anxiety disorder. Arch Inern Med. 2006;166:1092-1097)

[0130] Kidney Disease Quality of Life Short Form (KDQOL-SF): The KDQOL-SF is a self-report measure developed for individuals with kidney disease and those on dialysis. It includes 43 kidney disease -targeted items, such as the effects of the disease of activities of daily living, work status, and social interaction, and 36 items that provide a measure of physical and mental health, and 1 overall health rating item ranging from 0 ("worst possible health") to 10 ("best possible health.") (Hays RD, Kallich JD, Mapes DL, et al. Kidney Disease Quality of Life Short Form (KDQOL-SF), Version 1.3: a manual for use and scoring. Qual Life Res 1994;3:329-338). [0131] Simplified Nutritional Appetite Questionnaire (SNAQ): SNAQ is a designed to assess appetite among older adults. The questions with their topics can be described as follows: appetite, satiety, taste and the number of meals consumed during the day. Scoring ranges from 4 to 20 points. A cut-off score < 14 points indicates poor appetite with the risk of significant weight loss within 6 months (Wilson et al. Appetite assessment: simple appetite questionnaire predicts weight loss in community-dwelling adults and nursing home residents. Am J Clin Nutr. 2005;82(5):1074-1081. doi: 10.1093/ajcn/82.5.1074).

[0132] Modified Edmonton symptom assessment system (ESAS): The modified ESAS consists of 10 visual analogue scales with a superimposed 0-10 scale for pain, activity, nausea, pruritus, depression, anxiety, drowsiness, appetite, well-being and shortness of breath. The scale for each symptom is anchored by the words‘No’ and‘Severe’ at 0 and 10, respectively. Moderate intensity of any symptom is defined as 4-6 and severe as 7-10 on the Likert scale. A total symptom distress score is calculated by summing of the scores for all 10 symptoms on the ES AS (ranges from 0 to 100) (Sara N. Davison, Gian S. Jhangri, Jeffrey A. Johnson, Longitudinal validation of a modified Edmonton symptom assessment system (ESAS) in haemodialysis patients, Nephrology Dialysis Transplantation, Volume 21, Issue 11, November 2006, Pages 3189-3195, https://doi.org/10.1093/ndt/gfl380).

[0133] International Restless Legs Syndrome Study Group Rating Scale: is a a rating scale for measuring the severity of Restless Legs Syndrome (RLS). It consists of a 10-item questionnaire asks respondents to use Likert-type ratings to indicate how acutely the disorder has affected them over the course of the past week. Questions can be divided into one of two categories: disorder symptoms (nature intensity and frequency) and their impact (sleep issues, disturbances In daily functioning, and resultant changes in mood). Each of the ten questions requires respondents to rate their experiences with RLS on a scale from 0 to 4, with 4 representing the most severe and frequent symptoms and 0 representing the least. Total scores can range from 0 to 40 (The International Restless Legs Syndrome Study Group. Validation of the International Restless Legs Syndrome Study Group Rating Scale for Restless Legs Syndrome. Sleep Med. 2003;4(2): 121-132).

[0134] The frequency and severity of pain as well as symptoms of the kidney disease or side effects from opioids, including pruritus, quality of sleep, appetite, RLS, anxiety, fatigue, dyspnea, numbness in extremity, dizziness, confusion, memory problems, euphoria, restlessness, somnolence, vomiting, abdominal pain, diarrhea, tachycardia, chest pain, itching, dry mouth, respiratory problems, and recurrent infections, are monitored and compared between groups, when severity is classified as mild, moderate, or severe. REFERENCES

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Claims

1. A cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD) and D⁹-tetrahydrocannabinol (THC), or enantiomers, diastereomers, or racemates thereof, for use in the treatment of chronic pain and associated symptoms in a subject suffering from end- stage renal disease (ESRD) and treated with dialysis, wherein the CBD:THC weight ratio in the cannabinoid combination is about of 4:1 to about 10:1.

2. The cannabinoid combination for use of claim 1, wherein the CBD:THC weight ratio is about 6:1.

3. The cannabinoid combination for use of claim 1 or 2, formulated as a sole pharmaceutical composition, optionally further comprising a pharmaceutically acceptable carrier.

4. The cannabinoid combination for use of any one of claims 1-3, wherein the CBD is formulated for administration at a daily dose of about 15 mg to about 150 mg and the THC is formulated for administration at a daily dose of about 2.5 mg to about 25 mg.

5. The cannabinoid combination for use of any one of claims 1-4, wherein the cannabinoid combination is formulated for administration once, twice, or three times a day.

6. The cannabinoid combination for use of any one of claims 1-5, wherein the cannabinoid combination is formulated for administration sublingually, orally, or by inhalation.

7. The cannabinoid combination for use of any one of claims 1-6, wherein the chronic pain is associated with the ESRD itself, a background diseases, a complication of ESRD, a complication of the dialysis, or a side effect of a drug administered to treat any of the above diseases or complications or any symptoms associated with ESRD.

8. The cannabinoid combination for use of any one of claims 1-7, wherein the chronic pain is neuropathic pain, bone pain, abdominal pain, joint pain, and/or muscle pain.

9. The cannabinoid combination for use of any one of claims 1-8, wherein the associated symptoms are selected from depression, restless leg syndrome (RLS), nausea, constipation, vomiting, decreased or loss of appetite, a sleep disorder, pruritus, anxiety, fatigue, dyspnea, numbness in extremity, dizziness, confusion, memory problems, euphoria, restlessness, somnolence, vomiting, abdominal pain, diarrhea, tachycardia, chest pain, itching, dry mouth, respiratory problems, and recurrent infections.

10. The cannabinoid combination for use of any one of claims 1-9, wherein the subject suffers from at least one of depression, restless leg syndrome (RLS), nausea, constipation, vomiting, decreased or loss of appetite, a sleep disorder, pruritus anxiety, fatigue, dyspnea, numbness in extremity, dizziness, confusion, memory problems, euphoria, restlessness, somnolence, vomiting, abdominal pain, diarrhea, tachycardia, chest pain, itching, dry mouth, respiratory problems, and recurrent infections.

11. The cannabinoid combination for use of any one of claims 1-10, wherein the treatment provides an improvement in at least one disease parameter selected from pain, depression, anxiety, fatigue, dyspnea, numbness in extremity, dizziness, confusion, memory problems, euphoria, restlessness, somnolence, vomiting, abdominal pain, diarrhea, tachycardia, chest pain, itching, dry mouth, respiratory problems, recurrent infections, reduced, luality of life, quality of sleep, pruritus, nausea, constipation, appetite, and RLS.

12. The cannabinoid combination for use of claim 11, wherein the at least one disease parameter is measured by at least one method selected from: Generalized Anxiety Disorder scale (GAD-7), side effects questionnaire, Brief pain Inventory (BPI), Quality of Life Questionnaire for Dialysis Patients (KDQOL-SF), Symptom Burden Questionnaire Adjusted for Dialysis Patients (ESAS), Shortened Appetite Assessment Questionnaire, and RLS questionnaire.

13. The cannabinoid combination for use of claim 11 or 12, wherein the improvement is by at least 10%, 20%, 20%, 30%, 40%, 50%, 60%, or 70%.

14. The cannabinoid combination for use of any one of claims 1-13, wherein the subject is further receiving at least one analgesic.

15. The cannabinoid combination for use of claim 14, wherein the subject was non- responsive to an analgesic for at least one month during a time period prior to the treatment.

16. The cannabinoid combination for use of claim 14 or claim 15, wherein one or more of the at least one analgesic is an opioid.

17. The cannabinoid combination for use of any one of claims 14-16, wherein one or more of the at least one analgesic is administered at a dose lower than recommended by the manufacturer.

18. The cannabinoid combination for use of claim 17, wherein one or more of the at least one analgesic is administered at a sub-therapeutic dose.

19. A cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD) and A9-tetrahydrocannabinol (THC), or enantiomers, diastereomers, or racemates thereof, for use in improving the efficacy and/or for reducing adverse effects of at least one analgesic used for treating pain in a subject suffering from end-stage renal disease (ESRD) and treated with dialysis, wherein the CBD:THC weight ratio in the cannabinoid combination is about of 4:1 to about 10:1.

20. The cannabinoid combination for use of claim 19, wherein the CBD:THC weight ratio is about 6:1.

21. A method for treating chronic pain and associated symptoms in a subject suffering from end-stage renal disease (ESRD) and treated with dialysis, the method comprising administering to a subject in need thereof a therapeutically effective amount of a cannabinoid combination comprising cannabidiol (CBD) and A9-tetrahydrocannabinol (THC), or enantiomers, diastereomers, or racemates thereof, wherein the CBD and A9-THC are at a weight ratio of from about 4:1 to about 10:1.

22. A method for improving the efficacy and/or reducing adverse effects of at least one analgesic used for treating pain in a subject suffering from end-stage renal disease (ESRD) and treated with dialysis, the method comprising administering to the subject a therapeutically effective amount of a cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD) and A9-tetrahydrocannabinol (THC), or enantiomers, diastereomers, or racemates thereof, wherein the CBD:THC weight ratio in the cannabinoid combination is about of 4:1 to about 10:1.