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Cannabinoids

Open AccessPublished:May 28, 2013DOI:https://doi.org/10.1016/j.jpainsymman.2013.05.002
      Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativedrugs.com. The series editors welcome feedback on the articles ( [email protected] ).

      Abbreviations

      Off-label use
      5HT3
      5-hydroxytryptamine type 3 (receptor)
      AIDS
      Aquired immune deficiency syndrome
      b.i.d.
      Bis in die, twice daily
      CB1, 2
      Cannabinoid type 1, 2 (receptor)
      CBD
      Cannabidiol
      CNS
      Central nervous system
      COX
      Cyclo-oxygenase
      CYP450
      Cytochrome P450
      GABA
      Gamma-aminobutyric acid
      NNT
      Number needed to treat
      q3h, etc.
      Every 3 hours, etc.
      RCT
      Randomized controlled trial
      THC
      Tetrahydrocannabinol
      t.i.d.
      Ter in die, three times daily
      TRPV1
      Transient receptor potential channel (subfamily V member 1)
      v/v
      Volume/volume
      In the USA, only dronabinol and nabilone are available. For international educational and comparative purposes, this article also refers to formulations not available in the USA, e.g., nabiximols (Sativex®).

      Indications

      Chemotherapy-induced nausea and vomiting (dronabinol, nabilone); AIDS-related anorexia (dronabinol); refractory spasticity in multiple sclerosis (nabiximols); †pain unresponsive to standard treatments.
      Contraindications: history (including family history) of psychosis.

      Pharmacology

      Endocannabinoids have important regulatory roles throughout the nervous system, immune system, and elsewhere, making them a potential therapeutic target for a wide range of disorders, including nausea, pain, inflammation, cancer, cardiovascular disease, spasticity, epilepsy and immunomodulation.
      • Hill A.J.
      • Mercier M.S.
      • Hill T.D.
      • et al.
      Cannabidivarin is anticonvulsant in mouse and rat in vitro and in seizure models.
      • Preet A.
      • Qamri Z.
      • Nasser M.W.
      • et al.
      Cannabinoid receptors, CB1 and CB2, as novel targets for inhibition of non-small cell lung cancer growth and metastasis.
      • Torres S.
      • Lorente M.
      • Rodríguez-Fornés F.
      • et al.
      A combined preclinical therapy of cannabinoids and temozolomide against glioma.
      • Tanasescu R.
      • Constantinescu C.S.
      Cannabinoids and the immune system: an overview.
      • Stanley C.P.
      • Hind W.H.
      • O'Sullivan S.E.
      Is the cardiovascular system a therapeutic target for cannabidiol?.
      • Scotter E.L.
      • Abood M.E.
      • Glass M.
      The endocannabinoid system as a target for the treatment of neurodegenerative disease.
      • Castillo P.E.
      • Younts T.J.
      • Chávez A.E.
      • Hashimotodani Y.
      Endocannabinoid signaling and synaptic function.
      Currently available cannabinoids all contain the psychoactive constituent of Cannabis sativa, Δ9-tetrahydrocannabinol (Δ9-THC) or a synthetic analogue. They are generally less effective or less well tolerated than alternative drugs and are relatively expensive. Their use as antiemetics has been limited, and was rapidly eclipsed by the advent of 5HT3 antagonists. Although dronabinol reduced AIDS-related anorexia and weight loss, there was a trend towards more rapid deterioration in performance status.
      • Beal J.E.
      • Olson R.
      • Laubenstein L.
      • et al.
      Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS.
      In cancer-related anorexia, they were shown to be inferior to megestrol and no more effective than placebo.
      • Strasser F.
      • Luftner D.
      • Possinger K.
      • et al.
      Cannabis-In-Cachexia-Study-Group
      Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group.
      • Jatoi A.
      • Windschitl H.E.
      • Loprinzi C.L.
      • et al.
      Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study.
      Their analgesic effect is modest, and despite interest in their respiratory effects,
      • Ahmedzai S.
      Respiratory distress in the terminally ill patient.
      • Pickering E.E.
      • Semple S.J.
      • Nazir M.S.
      • et al.
      Cannabinoid effects on ventilation and breathlessness: a pilot study of efficacy and safety.
      benefit in breathlessness has not been confirmed by RCT.
      An improved understanding of the endocannabinoid system and Cannabis sativa’s many non-psychoactive compounds
      • Hill A.J.
      • Mercier M.S.
      • Hill T.D.
      • et al.
      Cannabidivarin is anticonvulsant in mouse and rat in vitro and in seizure models.
      • Izzo A.A.
      • Borrelli F.
      • Capasso R.
      • Di Marzo V.
      • Mechoulam R.
      Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb.
      has led to several developments in an attempt to improve effectiveness and tolerability:
      • CB2-selective agonists
        • Wilkerson J.L.
        • Gentry K.R.
        • Dengler E.C.
        • et al.
        Intrathecal cannabilactone CB(2)R agonist, AM1710, controls pathological pain and restores basal cytokine levels.
        • Gu X.
        • Mei F.
        • Liu Y.
        • et al.
        Intrathecal administration of the cannabinoid 2 receptor agonist JWH015 can attenuate cancer pain and decrease mRNA expression of the 2B subunit of N-methyl-D-aspartic acid.
      • peripherally-acting cannabinoids
        • Yu X.H.
        • Cao C.Q.
        • Martino G.
        • et al.
        A peripherally restricted cannabinoid receptor agonist produces robust anti-nociceptive effects in rodent models of inflammatory and neuropathic pain.
      • inhibitors of endocannabinoid breakdown
        • Roques B.P.
        • Fournié-Zaluski M.C.
        • Wurm M.
        Inhibiting the breakdown of endogenous opioids and cannabinoids to alleviate pain.
        • Huggins J.P.
        • Smart T.S.
        • Langman S.
        • Taylor L.
        • Young T.
        An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee.
      • combining cannabinoids with different properties, e.g., Δ9-THC with cannabidiol (CBD) (see below).
        • Barnes M.P.
        Sativex: clinical efficacy and tolerability in the treatment of symptoms of multiple sclerosis and neuropathic pain.

      Endocannabinoid System

      The endocannabinoid system comprises:
      • Rea K.
      • Roche M.
      • Finn D.P.
      Supraspinal modulation of pain by cannabinoids: the role of GABA and glutamate.
      • two known receptors
        • CB1, expressed mainly by central and peripheral neurons
        • CB2, expressed mainly by immune cells
      • endogenous cannabinoids (endocannabinoids), mainly fatty acids derived from arachidonic acid, produced de novo as required, and then rapidly removed by hydrolysis. Several have been identified, notably:
      • enzymes and uptake systems involved in endocannabinoid metabolism, including COX-2 and fatty acid amide hydrolase-1.
        • Roques B.P.
        • Fournié-Zaluski M.C.
        • Wurm M.
        Inhibiting the breakdown of endogenous opioids and cannabinoids to alleviate pain.
        • Huggins J.P.
        • Smart T.S.
        • Langman S.
        • Taylor L.
        • Young T.
        An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee.
      CB1 (an inhibitory receptor) reduces neuronal excitability and neurotransmitter release by opening potassium channels and blocking N/P/Q-type calcium channels, respectively. It is part of a negative feedback loop which regulates neurotransmitter release and thereby the function of various CNS circuits (Fig. 1). This part explains some of the antispasticity, analgesic and other effects of cannabinoids.
      • Rea K.
      • Roche M.
      • Finn D.P.
      Supraspinal modulation of pain by cannabinoids: the role of GABA and glutamate.
      • Pryce G.
      • Baker D.
      Control of spasticity in a multiple sclerosis model is mediated by CB1, not CB2, cannabinoid receptors.
      Figure thumbnail gr1
      Fig. 1Cannabinoids and neurotransmission. Endocannabinoids are retrograde neurotransmitters, traveling from the post- to the pre-synaptic neuron as part of a negative feedback loop that regulates neurotransmitter release. a. arriving action potential opens voltage-gated calcium channels; increasing pre-synaptic intracellular calcium triggers the release of stored neurotransmitter. Post-synaptic events depend on the neurotransmitter but include an increase in intracellular calcium. b. increasing post-synaptic intracellular calcium triggers the de novo synthesis of endocannabinoids from arachidonic acid. c. activation of CB1 closes pre-synaptic calcium channels preventing further calcium influx, thereby terminating neurotransmitter release. These channels are also targeted by other drugs of analgesic relevance, e.g., gabapentin, pregabalin, ziconotide. d. endocannabinoids removed by hydrolysis, e.g., fatty acid amide hydrolase-1.
      Central and peripheral CB1 receptors also modulate appetite and energy metabolism, respectively. CNS receptors are expressed on hypothalamic and limbic neurons; those in the periphery exist on adipocytes, skeletal muscle cells and hepatocytes. Activation of peripheral CB1 receptors promotes fat deposition and insulin resistance.
      • Tibirica E.
      The multiple functions of the endocannabinoid system: a focus on the regulation of food intake.
      Animal studies suggest that central and peripheral CB1 receptors also impact on the cardiorespiratory system. In the brainstem, CB1 stimulation elicits respiratory depression, bradycardia and hypertension.
      • Pfitzer T.
      • Niederhoffer N.
      • Szabo B.
      Central effects of the cannabinoid receptor agonist WIN55212-2 on respiratory and cardiovascular regulation in anaesthetised rats.
      In the lung, the effect is variable, with CB1 stimulation able to attenuate capsaicin-induced bronchoconstriction but also induce bronchoconstriction in vagotomized animals.
      • Calignano A.
      • Kátona I.
      • Désarnaud F.
      • et al.
      Bidirectional control of airway responsiveness by endogenous cannabinoids.
      CB2 is implicated in immune regulation. Located on antigen-presenting cells, it influences their cytokine profile and thus that of T-helper cells.
      • Tanasescu R.
      • Constantinescu C.S.
      Cannabinoids and the immune system: an overview.
      This may partly explain its anti-inflammatory and antihyperalgesic effects. Its expression on microglia is upregulated in the dorsal root ganglia and spinal cord following sciatic nerve injury. It also may be expressed on neurons.
      • Atwood B.K.
      • Mackie K.
      CB2: a cannabinoid receptor with an identity crisis.
      The antihyperalgesic effects of CB1 and CB2 activation are distinct and additive, and include:
      • Gutierrez T.
      • Farthing J.N.
      • Zvonok A.M.
      • Makriyannis A.
      • Hohmann A.G.
      Activation of peripheral cannabinoid CB1 and CB2 receptors suppresses the maintenance of inflammatory nociception: a comparative analysis.
      • peripheral immunomodulation (antigen-presenting cell CB2; interactions between immune cells and neurons contributes to peripheral sensitization and neuropathic pain)
        • Scholz J.
        • Woolf C.J.
        The neuropathic pain triad: neurons, immune cells and glia.
      • dorsal columns (microglial CB2)
      • disinhibition of antinociceptive neurons of a descending pain modulatory pathway (CB1 on the pathway’s GABAergic “brake”; cf. opioids).
        • Wilkerson J.L.
        • Gentry K.R.
        • Dengler E.C.
        • et al.
        Intrathecal cannabilactone CB(2)R agonist, AM1710, controls pathological pain and restores basal cytokine levels.
        • Gu X.
        • Mei F.
        • Liu Y.
        • et al.
        Intrathecal administration of the cannabinoid 2 receptor agonist JWH015 can attenuate cancer pain and decrease mRNA expression of the 2B subunit of N-methyl-D-aspartic acid.
        • Meng I.D.
        • Manning B.H.
        • Martin W.J.
        • Fields H.L.
        An analgesia circuit activated by cannabinoids.
        • Welch S.P.
        Interaction of the cannabinoid and opioid systems in the modulation of nociception.
      Further, unlike opioid receptors, CB1 persists in the spinal cord after peripheral nerve injury.
      • Farquhar-Smith W.P.
      • Rice A.S.
      Administration of endocannabinoids prevents a referred hyperalgesia associated with inflammation of the urinary bladder.
      • Hohmann A.G.
      • Herkenham M.
      Regulation of cannabinoid and mu opioid receptors in rat lumbar spinal cord following neonatal capsaicin treatment.
      Endocannabinoids also act at other receptors, including the capsaicin receptor (TRPV1, involved in pain signaling), and perhaps also G protein-coupled receptors 55 and 119.
      • Brown A.J.
      Novel cannabinoid receptors.

      Exogenous Cannabinoids

      Δ9-THC is a CB1 and CB2 partial agonist. Its effects include muscle relaxation, analgesia, antiemesis, but also psychosis, anxiety and sedation. Dronabinol is a synthetic preparation of its (-)-trans isomer, the best studied of several isomers present in Cannabis sativa; nabilone is a synthetic analogue.
      The effects of Δ9-THC are modified by other cannabinoids present in Cannabis sativa. For example, cannabidiol (CBD) reduces Δ9-THC-induced anxiety in healthy volunteers, perhaps by inhibiting the metabolism of Δ9-THC to a more psychoactive metabolite, 11-hydroxyTHC. CBD is also a CB1/CB2 antagonist; its apparently low affinity for both receptors suggesting non-competitive antagonism through a separate binding site. Although a less potent analgesic and antiemetic, CBD is anxiolytic, antipsychotic and non-sedating.
      • Russo E.
      • Guy G.W.
      A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol.
      • Fusar-Poli P.
      • Crippa J.A.
      • Bhattacharyya S.
      • et al.
      Distinct effects of {delta}9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing.
      In an attempt to improve the efficacy/tolerability profile of Δ9-THC, a formulation which combines Δ9-THC and CBD has been developed. Nabiximols, an extract of cannabis plants containing 2.7mg of Δ9-THC and 2.5mg of CBD in each oral spray, is commercially available for spasticity or pain in several countries. Results of RCTs comparing the Δ9-THC:CBD combination with Δ9-THC alone in patients with pain have been mixed; two found modest improvements in tolerability and patient preference,
      • Wade D.T.
      • Robson P.
      • House H.
      • Makela P.
      • Aram J.
      A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms.
      • 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.
      one found modest improvements in efficacy, but not tolerability,
      • Johnson J.R.
      • Burnell-Nugent M.
      • Lossignol D.
      • et al.
      Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC: CBD extract and THC extract in patients with intractable cancer-related pain.
      and one found no difference.
      • Berman J.S.
      • Symonds C.
      • Birch R.
      Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial.
      The non-psychoactive constituents of Cannabis sativa are poorly understood but they may interact with non-CB1/CB2 cannabinoid receptors and/or the metabolism of endocannabinoids.
      • Izzo A.A.
      • Borrelli F.
      • Capasso R.
      • Di Marzo V.
      • Mechoulam R.
      Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb.
      However, an RCT examining an inhibitor of endocannabinoid breakdown found no benefit for osteoarthritic pain.
      • Huggins J.P.
      • Smart T.S.
      • Langman S.
      • Taylor L.
      • Young T.
      An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee.
      The therapeutic potential of cannabinoid antagonists and inverse agonists also has been investigated. Rimonabant, a CB1 inverse agonist (i.e., results in a reduction in basal activity of the receptor), was approved for appetite suppression in obesity. However, it also caused depression, anxiety and aggression, and has been withdrawn.
      The pharmacokinetic profiles of selected cannabinoids are summarized in Table 1. Food increases the absorption of Δ9-THC and CBD oral spray, suggesting a proportion of the dose is swallowed before absorption.
      Table 1Pharmacokinetic Profiles of Selected Cannabinoids
      • Barnes M.P.
      Sativex: clinical efficacy and tolerability in the treatment of symptoms of multiple sclerosis and neuropathic pain.
      • Grotenhermen F.
      Pharmacokinetics and pharmacodynamics of cannabinoids.
      Oral Biovailability (%)Time to Peak Plasma Concentration (h)Half-life (h)Metabolism
      CannabidiolNot known1–45–9Multiple pathways
      Has active metabolite(s).
      ,
      Eliminated by both biliary and renal pathways.
      Nabilone851–42

      5–10
      Has active metabolite(s).
      Multiple pathways
      Has active metabolite(s).
      ,
      Eliminated by both biliary and renal pathways.
      Tetrahydrocannabinol≥501–42–5CYP2C9
      Affected by combined use: cannabidiol reduces Δ9-THC-induced anxiety in healthy volunteers, perhaps by inhibiting the metabolism of Δ9-THC to a more psychoactive metabolite, 11-hydroxyTHC.
      a Has active metabolite(s).
      b Eliminated by both biliary and renal pathways.
      c Affected by combined use: cannabidiol reduces Δ9-THC-induced anxiety in healthy volunteers, perhaps by inhibiting the metabolism of Δ9-THC to a more psychoactive metabolite, 11-hydroxyTHC.

      Cautions

      For full list, see manufacturers’ Prescribing Information.
      Psychiatric history (mood, cognitive and behavioral changes can occur); severe ischemic heart disease, heart failure or arrhythmias (risk of postural hypotension or reflex tachycardia); renal or hepatic impairment (no data, but active hepatic metabolites undergo biliary and renal clearance); epilepsy (cannabinoids can either lower or raise seizure threshold).

      Drug Interactions

      For full list, see manufacturers’ Prescribing Information.
      Additive CNS depressant effects with other psychotropics.
      Cannabinoids inhibit numerous CYP450 enzymes, although generally not at typical therapeutic concentrations. Caution is advised when substrates for CYP2C19, 2D6 (e.g., amitriptyline) and 3A4 (e.g., alfentanil, dofetilide, fentanyl, sufentanil) are used concurrently with nabiximols.
      The metabolism of nabiximols is marginally inhibited by CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole, ritonavir) and may be induced by CYP3A4 inducers, (e.g., carbamazepine, rifampin).

      Undesirable Effects (Box A)

      These vary between cannabinoids; for full list, see manufacturers’ Prescribing Information.
      Undesirable Effects of Cannabinoids
      Psychologicala
      Common (<10%, >1%): depression, euphoria, disorientation, dissociation
      Uncommon (<1%, >0.1%): hallucinations, paranoia, delusions, suicidal ideation
      Neurologicalb
      Very common (>10%): dizziness (nabiximols, particularly during titration)
      Common: ataxia, amnesia, drowsiness, blurred vision
      Gastrointestinalc
      Common: appetite (↑ or ↓), nausea
      Uncommon: abdominal pain
      Cardiovascular
      Uncommon: palpitations, tachycardia, syncope, hyper/hypotension
      Buccal irritationd (nabiximols only)
      Common: ulceration, pain
      Uncommon: discoloration
      aIllicit use is a risk factor for schizophrenia.
      • Malone D.T.
      • Hill M.N.
      • Rubino T.
      Adolescent cannabis use and psychosis: epidemiology and neurodevelopmental models.
      bTolerance to CNS depressant effects generally develops after a few days.
      cDelayed onset nausea and vomiting (“cannabinoid hyperemesis”) are described with illicit use of Cannabis sativa. Symptoms are generally worst in the morning (70%), associated with abdominal colic (86%), and resolve when the cannabinoid is discontinued. Although most patients have used cannabis weekly for at least 2 years before symptom onset, a third have symptoms within one year.
      • Simonetto D.A.
      • Oxentenko A.S.
      • Herman M.L.
      • Szostek J.H.
      Cannabinoid hyperemesis: a case series of 98 patients.
      dNabiximols contains 50% v/v ethanol and propylene glycol. Two reports of suspected leukoplakia occurred in RCTs.

      Use of Cannabinoids in Palliative Care

      Chemotherapy-induced Nausea and Vomiting (Dronabinol, Nabilone)

      Although cannabinoids have some antiemetic efficacy in moderately emetogenic chemotherapy regimens (see Prescribing Information for details), 5HT3 antagonists, which are more effective and better tolerated, are generally used instead.
      • Davis M.P.
      Oral nabilone capsules in the treatment of chemotherapy-induced nausea and vomiting and pain.
      The manufacturer advises against the use of nabilone for non-chemotherapy related nausea.

      AIDS-related Anorexia (Dronabinol)

      In cancer-related anorexia, cannabinoids are inferior to megestrol and no more effective than placebo.
      • Strasser F.
      • Luftner D.
      • Possinger K.
      • et al.
      Cannabis-In-Cachexia-Study-Group
      Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group.
      • Jatoi A.
      • Windschitl H.E.
      • Loprinzi C.L.
      • et al.
      Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study.
      • 2.5mg PO b.i.d., generally before lunch and dinner
      • if undesirable effects occur which do not resolve within 3 days of continued use, reduce dose to 2.5mg before dinner (or at bedtime)
      • if tolerated but ineffective, consider gradually increasing the dose to a maximum of 20mg/24h.

      Refractory Spasticity in Multiple Sclerosis (Nabiximols)

      • start with 1 spray at bedtime
      • increase over 2 weeks to a maximum of 12 sprays/24h given in divided doses, e.g., 1–2 sprays b.i.d.−3 sprays q.i.d.
      • because food can increase drug absorption, consistent timing of administration with regard to mealtimes might be an important consideration in some patients.
      Direct spray beneath the tongue or inside the cheeks (not towards the pharynx). Vary the site and inspect buccal mucosa regularly for signs of irritation caused by the excipients, ethanol (50%v/v) and propylene glycol.

      Refractory Pain (Nabiximols, Nabilone)

      Generally, such use is off-label. In Canada, nabiximols is approved under the Notice of Compliance with Conditions for neuropathic pain in multiple sclerosis and for cancer pain unresponsive to the optimal use of strong opioids. Nabiximols also is approved in the U.K. and Israel.
      A systematic review found moderate benefit for a variety of non-cancer pains (NNT 3.5–9 for 30% pain reduction). Oromucosal cannabis extracts, nabilone, smoked cannabis and dronabinol were effective for neuropathic pain, fibromyalgia, and painful spasticity. Undesirable effects were generally mild.
      • Lynch M.E.
      • Campbell F.
      Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials.
      • Toth C.
      • Mawani S.
      • Brady S.
      • et al.
      An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain.
      • Langford R.M.
      • Mares J.
      • Novotna A.
      • et al.
      A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis.
      Most trials were short (<6 weeks) but open-label extension studies found that analgesia was maintained without dose escalation for up to 1.5 years.
      • Wade D.T.
      • Makela P.M.
      • House H.
      • Bateman C.
      • Robson P.
      Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis.
      • Nurmikko T.J.
      • Serpell M.G.
      • Hoggart B.
      • et al.
      Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial.

      Johnson JR, Lossignol D, Burnell-Nugent M, Fallon MT. An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manage 2012 Nov 7. [Epub ahead of print].

      Two RCTs have examined nabiximols for intractable cancer pain with mixed results. In one, it was more effective than placebo or Δ9-THC alone (NNT 4.5 for 30% pain reduction) but withdrawal due to undesirable effects was three-times higher with nabiximols than placebo (17% vs. 5%).
      • Johnson J.R.
      • Burnell-Nugent M.
      • Lossignol D.
      • et al.
      Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC: CBD extract and THC extract in patients with intractable cancer-related pain.
      The other study found no difference between nabiximols and placebo in the primary endpoint of the proportion of patients reporting ≥30% reduction in pain. However, this was a graded dose study, which did not include titration to an optimal effect.
      • Portenoy R.K.
      • Ganae-Motan E.D.
      • Allende S.
      • et al.
      Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial.
      Nabiximols (adapted from the Canadian Product Monograph)
      • start with 1 spray up to q4h (maximum 4 sprays in the first 24h)
      • titrate up on a daily basis (but more slowly if dizziness occurs)
      • most patients require ≤12 sprays/24h (median dose = 5–8 sprays/24h).
      For general use of nabiximols, see above.
      NabiloneNote. Only a 1mg capsule is available in the U.S.; lower strength capsules, e.g., 0.25mg, 0.5mg, are available in other countries, including Canada.

      Supply

      Dronabinol
      A schedule III controlled substance.
      Dronabinol (generic)
      Capsules (all contain sesame oil) 2.5mg, 5mg, 10mg, 30 days @ 2.5mg b.i.d. = $207.
      Marinol® (Roxane)
      Capsules (all contain sesame oil) 2.5mg, 5mg, 10mg, 30 days @ 2.5mg b.i.d. = $549.
      Nabilone
      A schedule II controlled substance.
      Cesamet® (Valeant Pharmaceuticals)
      Capsules 1mg, 30 days @ 1mg b.i.d. = $1,680.

      References

        • Hill A.J.
        • Mercier M.S.
        • Hill T.D.
        • et al.
        Cannabidivarin is anticonvulsant in mouse and rat in vitro and in seizure models.
        Br J Pharmacol. 2012; 167: 1629-1642
        • Preet A.
        • Qamri Z.
        • Nasser M.W.
        • et al.
        Cannabinoid receptors, CB1 and CB2, as novel targets for inhibition of non-small cell lung cancer growth and metastasis.
        Cancer Prev Res (Phila). 2011; 4: 65-75
        • Torres S.
        • Lorente M.
        • Rodríguez-Fornés F.
        • et al.
        A combined preclinical therapy of cannabinoids and temozolomide against glioma.
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