Clearing the smoke: nabiximols, a pharmaceutical cannabinoid, as adjunct therapy for cancer pain

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1 Clearing the smoke: nabiximols, a pharmaceutical cannabinoid, as adjunct therapy for cancer pain Amanda Basto, Pharm.D. PGY-1 Pharmacy Practice Resident Central Texas Veterans Health Care System University of Texas at Austin College of Pharmacy December 13, 2013 Learning Objectives 1. Review the epidemiology, causes, and treatment standards of cancer-related pain 2. Discuss the endocannabinoid system and pharmacologic utilization of cannabinoids in pain 3. Evaluate literature on nabiximols and its use in cancer-related pain 4. Analyze the safety implications of nabiximols based on currently available literature Basto 1

2 I. Pain definition: an unpleasant, multidimensional, sensory, and emotional experience associated with actual or potential tissue damage, or described in relation to such damage (International Association for the Study of Pain) I. Epidemiology a. Incidence of cancer 2,8 i. >10 million people worldwide are diagnosed with cancer every year ii. 1.6 million cases in the United States expected to be diagnosed in 2013 b. Prevalence of pain 8,12 i. 50% of patients report having pain at any stage of cancer ii % of patients with metastatic/advanced cancer report pain iii. Highest to lowest prevalence: bone, pancreatic, stomach, uterus/cervix, lung, breast, prostate, colon, lymphoma, leukemia c. Pain can be a first sign of cancer that causes the patient to seek medical attention d. Evidence has suggested that survival is linked to effective pain control 20 e. 43% of cancer patients are undertreated for pain 4 II. Causes 8,21 a. Pain from tumor i. Nociceptive primary afferent sensory neurons (C and Aδ fibers) carry pain signals from peripheral tissues to spinal cord and brain; tissue injury from tumor cells peripheral sensitization resulting in hyperalgesia and allodynia 1. Somatic skin, bone 2. Visceral internal organs ii. Neuropathic neuronal injury from tumor invasion 1. Sensation of tingling, burning, heat/cold insensitivity associated with nerve compression or injury b. Treatment-related i. Chemotherapy-induced mucositis ii. Chemotherapy-induced peripheral neuropathy (CIPN) from offending agents: vinca-alkaloids, platinum, taxanes, thalidomide, bortezomib, radiation 1. Damage to C and Aδ fibers cold and mechanical allodynia 2. Damage to Aβ fibers parasthesias, dysesthesias, decreased proprioception c. Post-operative pain i. Perioperative nerve damage can manifest as neuropathic-like pain ii. Most commonly described in breast cancer, thoracotomy, and head and neck surgery III. Clinical evaluation 9 a. Pain should be assessed at each visit b. Assessment should focus on type and quality of pain, pain history, intensity, location, radiation, factors that exacerbate or relieve the pain, breakthrough pain c. Assessment methods i. Numerical Rating Scale (NRS) ii. Figure 1. Numerical rating scale example INTRODUCTION CANCER-RELATED PAIN NRS Score Pain classification 1-3 Mild 4-6 Moderate 7-10 Severe Basto 2

3 iii. Faces Pain Rating Scale Figure 2. Faces pain rating scale example IV. Treatment & standard of care a. Goals of therapy i. Improved comfort and function b. Guidelines i. World Health Organization (WHO) 21 3 step algorithm Figure 3. WHO Three-step algorithm ii. National Cancer Comprehensive Network (NCCN) 9 1. Algorithms are available in guidelines to guide opioid treatment in opioid naïve and opioid tolerant patients Table 1. Classification of opioid naïve and tolerant patients Opioid naïve Opioid tolerant Do not meet the Patient is taking at least: definition of opioid 60 mg/day oral morphine tolerant 25 mcg/hr transdermal fentanyl 30 mg/day oral oxycodone 8 mg/day oral hydromorphone Or equianalgesic dose of another opioid for one week or longer 2. Management of adult cancer pain a. Opioids are the principle analgesics for moderate to severe pain i. General principles: use of oral formulation when possible, around the clock coverage for persistent pain with breakthrough when needed, bowel regimen b. See Appendix B (p. 17) for opioid characteristics Basto 3

4 i. Adverse effects constipation, pruritus, delirium, motor/cognitive impairment, sedation, respiratory depression c. Adjuvant analgesics help manage bone pain, neuropathic pain, and visceral pain, and to reduce opioid requirement i. Anticonvulsants gabapentin, pregabalin ii. Antidepressants selective norepinephrine reuptake inhibitors (duloxetine, venlafaxine), tricyclic antidepressants (amitiptyline, nortriptyline, imipramine, desipramine) iii. Corticosteroids iv. Local/topical anesthetics - lidocaine ENDOCANNABINOID SYSTEM I. Two cannabinoid receptors identified in the human body 15 a. G-protein coupled receptors Table 2. Locations of cannabinoid receptors throughout the body Receptor Locations Effect CB 1 Cortex Basal ganglia, cerebellum Medulla Hippocampus Thalamus Amygdala Periaqueductal grey matter Substantia gelatinosa (spinal cord) Spinal cord dorsal horn A fibers > C fibers Cognition Movement Nausea/vomiting Learning, memory, stress Pain processing Pain processing, anxiety Pain processing Pain processing Pain processing Pain processing CB 2 Peripheral lymphoid and immune tissues Mediation of pain and inflammatory processes II. III. Endogenous cannabinoids activity in glutamatergic and GABA-ergic synapses neuromodulation in brain a. Anandamide b. 2-arachidonylglycerol (2-AG) Phytocannabinoids a. Delta-9-tetrahydrocannabinol (THC) i. Psychoactive effects ii. Partial agonist CB 1 > CB 2 iii. Anti-inflammatory: inhibition of PGE-2 synthesis, decreased platelet aggregation, stimulation of lipooxygenase b. Cannabidiol (CBD) i. Lacks psychoactive effects ii. Activity at vanilloid receptor type 1 and 5-HT 1A receptors iii. Neuroprotective effects iv. Antioxidant activity v. In-vitro studies show inhibition first pass metabolism of THC 11-hydroxy-THC (psychoactive) reducing effects of anxiety, intoxication, panic, tachycardia 22 Basto 4

5 c. Over 60 other phytocannabinoids have been identified IV. Relationship to pain and inflammation 10,11 a. Cannabis has been documented in the use of pain in ancient China and other countries b. Antinociceptive effects anatomical location of CB 1 receptors in areas of the CNS that are relevant to pain (Spinal dorsal horn, dorsal root ganglia, peripheral afferent neurons) i. Activation of CB 1 receptors decrease neurotransmitter release involved in pain transmission in rat studies 23 c. CBD found to inhibit CIPN in animal studies - 5HT 1A receptor agonist, vanilloid receptor type 1 binding which modulates nociception 24 d. Relationship between cannabinoid agonists and endogenous opioids i. Possible augmentation between endocannabinoid and opioid system suggested by animal and human studies 1 1. Cannabinoid agonists may release endogenous opioids ii. Stimulation of beta-endorphin production which could help prevent development of tolerance and withdrawal from opiates 3 I. Synthetic cannabinoids Table 3. FDA approved synthetic cannabinoids Drug Cannabinoid FDA Approved Use Schedule Dronabinol (Marinol) THC Nausea associated with chemotherapy Appetite stimulation in HIV/AIDS III Nabilone (Cesamet) PHARMACEUTICAL CANNABINOIDS THC Nausea associated with chemotherapy II II. Plant derived cannabinoids - Nabiximols (Sativex ) a. Developed by GW Pharmaceuticals (UK) b. Approved for use in 23 countries for spasticity associated with multiple sclerosis c. Formulation 16 i. Oromucosal spray buccal ii. 2.7 mg THC & 2.5 mg CBD per spray 1. Extracted from Cannabis sativa L. iii. Dosing 1. Patients self-titrate to effect over 2 week period- usually 4-8 sprays/day 2. No maximum listed in product monograph - not well studied in patients using > 12 sprays daily d. Pharmacokinetics 5 i. Onset of action: minutes ii. Duration of action 1. THC, t 1/2 = 85 minutes hydroxy THC, t 1/2 = 130 minutes 3. CBD, t 1/2 = 100 minutes iii. Metabolism 1. Hepatic cytochrome p450 enzymes a. Weak inhibition of CYP1A2, CYP2C6, CYP2D6, CYP2C19, CYP3A4 iv. Drug interactions 1. Drugs metabolized by the above enzymes 2. One published study with 3A4 & 2C19 inhibitor and inducers 18 Basto 5

6 a. Consideration of increased risk of adverse effects of nabiximols is required for strong 3A4 inhibitors/inducers LITERATURE REVIEW I. Areas of research Animal studies Pain Neuropathic Inflammatory Cancer Epilepsy Inflammation Metabolic syndrome Cannabis studies HIV-associated neuropathy Chronic neuropathic pain Pharmaceutical studies Nausea/vomiting Appetite stimulation Multiple sclerosis Spasticity Neuropathic pain Cancer pain II. III. Place in therapy a. Use of nabiximols in multiple sclerosis (see appendix D) i. Studies show efficacy in spasticity associated with MS ii. Other studies looking at neurogenic bladder, neuropathic pain b. Adjunct to opioids for cancer pain i. Seeking FDA approval Safety concerns a. Cannabis derived most widely used illicit substance worldwide i. Schedule I United States Controlled Substances Act High potential for abuse 2. No currently accepted medical use in treatment in the United States 3. Lack of accepted safety for use of the drug under medical supervision ii. Undesirable effects with smoked cannabis 1. Cognitive impairment, anxiety, paranoia, chronic psychosis b. Abuse and dependence potential of nabiximols due to psychoactive effects of cannabis i. Physiological vs. psychological dependence ii. Favorable abuse potential of nabiximols when compared with smoked cannabis Longer time required to reach peak concentration 2. Peaks at much lower concentration Table 4. Pharmacokinetics of smoked cannabis versus nabiximols Smoked cannabis Nabiximols Dose received by subjects Eight inhalations 33.8 mg THC 12.5 sprays 33.8 mg THC Max plasma calculated (ng/ml) Tmax (minutes) Basto 6

7 Portenoy RK, et al. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain. 2012;13: Purpose Design Subjects Endpoints Methods To obtain information about dose response for analgesia and safety in a population with medical illness and pain that is not adequately controlled with opioids Multicenter, randomized, double-blind, placebo-controlled, parallel group, graded-dose design to evaluate the analgesic efficacy and safety of nabiximols in 3 dose ranges Inclusion Exclusion Active cancer On long term methadone therapy Moderate or severe chronic pain Major cardiovascular or psychiatric disorder (NRS score 4-8) Significant renal or hepatic impairment On opioid regimen that could not Pregnant, lactating, not using adequate be made more effective by contraception further opioid dose titration Currently using or had used marijuana, cannabinoid-based medications or rimonabant within 30 days of study entry, Primary Pain response status positive response status 30% reduction in mean NRS pain score and unwilling to abstain for study duration Secondary Continuous responder rates Change in mean daily NRS score for average pain Change in mean daily NRS pain score for worst pain Sleep disruption PAC-QoL MADRS Intervention Randomization into low (1-4 sprays/day), medium (6-10 sprays/day) and high (11-16 sprays/day) dose groups vs. placebo in 1:1:1:1 ratio 1 week titration period with specific schedule, then stable daily dosing for 4 weeks Patients received daily call via interactive voice recording system to record doses of study medication used, average pain and worst pain on NRS scale, sleep disruption, fixed-dose and breakthrough pain medication use Statistical Analysis Primary efficacy endpoints: Intention-to-treat analysis Logistic regression - region and treatment as factors Secondary efficacy endpoints: analysis of covariance (ANCOVA) Basto 7

8 Results Baseline Characteristics Low Medium High Placebo (1-4 sprays) (6-10 sprays) (11-16 sprays) n n, completed Age 59 (12.3) 59 (13.1) 58 (11.2) 56 (12.2) Previous cannabis use 11 (12.1%) 11 (12.5%) 10 (11.1%) 6 (6.6%) Average baseline pain Fixed dose opioids, 120 (3, 16660) 120 (0, 2040) 180 (0, 2520) 120 (0, 1104) median (range) Treatment differences/odd ratios (p-value) Authors conclusions Critique Low (1-4 sprays) Medium (6-10 sprays) High (11-16 sprays) 30% Responder rate 1.37 (0.33) 1.19 (0.61) 0.90 (0.76) Daily average pain -0.75(0.006) -0.36(0.187) -0.09(0.75) NRS Daily mean worst -0.73(0.011) -0.24(0.397) -0.06(0.829) pain NRS Sleep disruption NRS -0.88(0.003) -0.33(0.26) -0.08(0.784) Cumulative -12.5(0.008) -8.75(0.038) -1.97(0.675) responder analysis No statistically significant difference in PAC-QoL or MADRS across groups Adverse Events, n (%) 1-4 sprays 6-10 sprays sprays Placebo Patients with AEs 70 (76.9) 74 (85.1) 83 (92.2) 71 (78) Serious treatment-emergent AEs Death 34 (37.4) 25 (27.5) 18 (20.7) 14 (16.1) 27 (30) 17 (18.9) 22 (24.2) 16 (17.6) Discontinuation due to AEs 13 (14.3) 15 (17.2) 25 (27.8) 16 (17.6) Common treatment-emergent AEs Nausea Dizziness Vomiting Somnolence 16 (17.6) 10 (11) 9 (9.9) 8 (8.8) 18 (20.7) 21 (24.1) 14 (16.1) 16 (18.4) 25 (27.8) 20 (22.2) 19 (21.1) 15 (16.7) 12 (13.2) 12 (13.2) 7 (7.7) 4 (4.4) Serious treatment-emergent AEs only deaths were reported None of the deaths were determined to be related to study drug Nabiximols has analgesic efficacy when used as add-on therapy in a population of cancer patients with pain that is poorly responsive to opioids High dose nabiximols did not show an analgesic effect and was not well tolerated Strengths Limitations Offers information regarding dose Missing data response Primary efficacy endpoint was not statistically Met power significant Adverse events listed in detail Forced dose design does not mirror self-titration instructions in package labeling Lacking external validity by exclusion of multiple disease states in an advanced cancer state Basto 8

9 Johnson JR, 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. J Pain Symptom Manage. 2010;39: Purpose Design Subjects Endpoints Methods To assess the analgesic efficacy of THC:CBD and THC extracts compared to placebo in the management of patients with at least moderately severe cancer-related pain despite appropriate pharmacological management Multicenter, double-blind, randomized, placebo-controlled, parallel-group study Inclusion criteria Adult male or female Had been using strong opioids for at least one week to relieve pain associated with incurable malignancy and who gave written informed consent Pain severity score of 4 or more on 0-10 NRS on both days of the two-day baseline period Primary Change from baseline in NRS pain score Use of breakthrough analgesia Exclusion criteria Cancers of oral cavity Major psychiatric or cardiovascular disorders Epilepsy Renal or hepatic impairment Pregnant, lactating, without adequate contraception Had received epidural analgesia within 48 hours of screening, palliative radio-, chemo-, hormonal therapy within 2 weeks of screening, CBs within seven days of randomization Concurrent use of fentanyl, levodopa, sildenafil Secondary Use of opioid background medication Patient assessment of sleep quality Nausea, memory, concentration, and appetite over the previous 24 hours using diary NRS Intervention Patients randomized to one of three treatment groups in 1:1:1 ratio: THC:CBD extract (2.7mg:2.5mg/spray), THC extract (2.7 mg/spray), Placebo spray Self-titration to optimal dose over week 1- could increase the total number of sprays each day by a maximum of 50% until satisfactory relief of symptoms or development of unwanted effects Maximum permitted dose: 8 actuations in any 3 hour period or 48 actuations in any 24 hour period Brief Pain Inventory-Short Form (BPI-SF) and The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) Version 3 were completed at visit 1 and end of study Patients completed study diary recording pain score three times daily, background medication, breakthrough analgesia daily during baseline period and throughout the study Statistical Analysis Intention-to-treat analysis of covariance (ANCOVA) with baseline pain as a covariate and grouped study center and treatment as factors Basto 9

10 Results Baseline characteristics THC:CBD THC Placebo n n, completed Male, n (%) 33 (55) 30 (52) 32 (54) Previous cannabis use, n (%) 6 (10) 6 (10) 7 (12) Age, mean (SD) 59.4 (12.1) 61.3 (12.5) 60.1 (12.3) Pain classification, n (%) Mixed Bone Neuropathic Visceral Somatic/incident Baseline morphine equivalents Median (mg) Range Mean (SD) 31 (52) 16 (27) 11 (18) 14 (23) 7 (11) (789.5) 28 (48) 24 (41) 11 (19) 12 (21) 5 (9) (234.5) 30 (51) 25 (42) 17 (29) 11 (19) 6 (10) (699) Endpoints THC:CBD n = 60 THC n = 58 Placebo n = 59 Mean no. sprays/day (SD) 9.26 (5.53) 8.47 (5.46) (5.81) Adjusted mean reduction in NRS (p = 0.014) (p = 0.245) Reduction in pain intensity 30% Odds ratio p-value 23 (43%) 2.81 (1.22, 6.5) (23%) 1.10 (0.44, 2.73) (21%) Breakthrough medication Baseline from baseline Treatment difference from placebo (p = 0.69) (p = 0.90) Use of strong opioid breakthrough medication, n (%) Increase No change Decrease Background medication, n (%) Increase No change Decrease Sleep quality (Mean NRS) Baseline Treatment difference from placebo n = 22 2 (9) 12 (56) 8 (36) 6 (12) 41 (79) 5 (10) (p = 0.346) n = 18 4 (22) 10 (56) 4 (22) 6 (12) 40 (77) 6 (12) (p = 0.95) n = 19 7 (37) 12 (63) 0 4 (7) 43 (80) 7 (13) 4.17 Basto 10

11 Safety/Adverse effects (p <0.05) Concentration (Mean NRS) Baseline Change from baseline Treatment difference from placebo Memory (Mean NRS) Baseline Change from baseline Treatment difference from placebo Cognitive functioning (Mean QLQ- C30) Baseline Change from baseline Treatment difference from placebo Nausea & vomiting (Mean QLQ- C30) Baseline Change from baseline Treatment difference from placebo THC:CBD THC Placebo (p = 0.021) (p = 0.045) (p = 0.022) (p = 0.02) (p = 0.028) (p = 0.053) (p = 0.008) (p = 0.997) Authors conclusions Critique Treatment related AEs reported by 60% of patients Rates of death similar across treatment groups, not attributed to study medication THC:CBD extract is an efficacious adjunctive treatment for cancer-related pain in patients with advanced cancer who are not achieving adequate analgesic response to opioids No safety concerns were identified during the study Strengths Limitations Both parametric/non-parametric analyses Narrow patient selection applied Difference in baseline opioid use less with Comparison to THC-only spray in addition THC:CBD group to placebo offers information on CBD Short treatment duration studied Basto 11

12 Johnson JR, et al. An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manage. 2013;46: Purpose Design Subjects Endpoints Methods Results To collect safety and tolerability data for long-term exposure to THC:CBD spray and THC spray Open-label, follow-up study of parent randomized, controlled trial (RCT) Inclusion criteria Exclusion criteria Completed parent study without Same as parent study unacceptable adverse effect Efficacy BPI-SF scores EORTC QLQ-C30 scores Safety Incidence of nonelicited AEs Laboratory parameters Use of rescue medication Maintenance analgesic medication Intervention Patients completing parent RCT invited to continue with THC:CBD or THC only spray Visits at end of parent RCT, then 7-10 days, then every 4 weeks until study completion or withdrawal Statistical Analysis No hypothesis testing Descriptive statistics n = 43 patients enrolled Treatment duration (days) Median Range Reasons for withdrawing (n) Adverse event Withdrew consent Lack of efficacy Lost to follow up Other THC:CBD (n = 39) THC (n = 4) Basto 12

13 Authors conclusions Critique No changes in functional status domains, except for worsening in physical functioning Common adverse events: dizziness, nausea & vomiting, dry mouth, somnolence Death: 12 (31%) THC:CBD, 1 (25%) THC only Study design limitations are acknowledged Suggest that THC:CBD spray remains well tolerated and beneficial for up to 5 weeks Results suggest continued efficacy and patients did not require dose escalation Strengths Limitations Sought to investigate limitation of short Unspecified study duration treatment duration in parent study Difficulty in drawing conclusions with data Data related to adverse events presentation and descriptive statistics Efficacy data mixed both THC/CBD and THC groups Advanced disease No comparison to placebo Basto 13

14 Schoedel KA, et al. A randomized, double-blind, placebo-controlled, crossover study to evaluate the subjective abuse potential and cognitive effects of nabiximols oromucosal spray in subjects with a history of recreational cannabis use. Hum Psychopharmacol Clin Exp. 2011;26: Purpose Design Subjects Endpoints Methods To evaluate the abuse potential and cognitive effects of nabiximols compared with dronabinol and placebo Single-dose, randomized, double-blind, balanced, placebo-controlled, crossover study Inclusion Exclusion Healthy male and female volunteers Drug or alcohol dependence Frequent recreational cannabis users (at Previously enrolled in drug rehabilitation program least once a week in the 3 months prior, Heavy consumers of caffeine and heavy smokers at least 4 times a week on at least one occasion) Positive urine THC drug test result Negative for other drugs of abuse and alcohol Primary Drug Liking Visual analogue scale (VAS) Subjective drug value (SDV) Addiction Research Center Inventory Morphine Benzedrine Group (ARCI MBG) Secondary ARCI LSD, PCAG, BG VAS several Choice Reaction Test (CRT), Divided Attention Test (DAT) Pharmacokinetics Blood samples for THC, CBD, 11-hydroxy-THC assays predose, 1.5, 4.5, 8.5 hours post-dose Safety Vital signs, 12-lead ECG, clinical laboratory tests, adverse events, telemetry for 8 hours post dose Intervention Qualification session with crossover between dronabinol 30mg and placebo Each subject participated in all six treatment sessions double-dummy 7-21 days between sessions Statistical Analysis Primary outcomes: Linear mixed-effect analysis of variance/covariance PK/PD: completed all treatment sessions (per protocol) Safety: took at least one dose of study drug Basto 14

15 Results Authors conclusions Critique n = 30 received at least one dose of study drug Treatment Drug Liking VAS AUE 24 SDV Emax ARCI MBG AUE 24 Placebo N 10.8 mg N 21.6 mg * 69.4 N 43.2 mg ** 13.8 ** 81.6 * D 20 mg ** ** 68.5 D 40 mg ** ** 81.7 * * p < 0.05 **p < Secondary Endpoints CRT & DAT: p > 0.05 STM: No significant difference between any treatment drug with placebo, except dronabinol 40 mg Adverse events: arrhythmia (1) with nabiximols 10.8 mg The abuse potential of nabiximols is no higher than that of dronabinol Strengths Number of subjects consistent with abuse potential studies Design consistent with abuse potential studies Limitations No titration of study medications Only heavy cannabis users studied Exclusion of drug and alcohol dependence Conclusions I. Efficacy a. Results of available studies are inconsistent but suggest that nabiximols may have a role in adjunct therapy to opioids for treatment of cancer pain b. Role of cannabinoids in pain control warrant further study with well-designed RCTs c. Doses greater than 10 sprays/day (27 mg THC/25 mg CBD) have not been shown to be effective for cancer pain and have increased adverse effects II. Safety a. Abuse potential is likely no greater than dronabinol, a schedule III medication. However, this should be confirmed in future studies b. Tolerance and withdrawal data from use in cancer pain is lacking c. Adverse effects are apparent and lead to discontinuation of drug. If FDA approved, AEs, especially affecting cognition, must be weighed into clinical picture surrounding improvement of quality of life III. Future directions a. Currently in phase III trials for cancer pain i. SPRAY III Trial (Sativex for Pain Research in Malignancy) ClinicalTrials.gov NCT b. Studies should look at impact on reducing opioid dosing, tolerance and withdrawal, other pain types IV. Bottom line a. Existing literature is only preliminary, and revisitation of this topic is warranted upon completion of Phase III trials Basto 15

16 References 1. Abrams DI, Couey P, Shade SB, et al. Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther. 2011;90: American Cancer Society. Cancer facts and figures Available at Accessed on November 17, Cichewicz DL, McCarthy EA. Antinociceptive synergy between delta(9)-tetrahydrocannabinol and opioids after oral administration. J Pharmacol Exp Ther. 2003;304: Deandrea S, Montanari M, Moja L et al. Prevalence of undertreatment in cancer pain. A review of published literature. Ann Oncol. 2008;19: Guy GW, Robson PJ. A phase I, double-blind, three-way crossover study to assess the pharmacokinetic profile of cannabis based medicine extract (CBME) administered sublingually in variant cannabinoid ratios in normal healthy male volunteers. J Cannabis Ther. 2004;3: Johnson JR, 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. J Pain Symptom Manage. 2010;39: Johnson JR, et al. An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manage. 2013;46: Mantyh PW. Cancer pain and its impact on diagnosis, survival and quality of life. Nature Reviews Neuroscience. 2006;7: National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Adult Cancer Pain (Version ). Accessed on October 26, Pacher P, Batkai S, Kunos G. The endocannabinoid system as an emerging target in pharmacotherapy. Pharmacol Rev. 2006;58: Pertwee RG. Cannabinoid receptors and pain. Progress in Neurobiology. 2001;63: Portenoy RK. Cancer pain: epidemiology and syndromes. Cancer. 1989;63: Portenoy RK, Ganae-Motan ED, Allende S, et al. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain. 2012;13: Robson P. Abuse potential and psychoactive effects of delta-9-tetrahydrocannabinol and cannabidiol oromucosal spray (Sativex), a new cannabinoid medicine. Expert Opin. Drug Saf. 2011;10: Russo EB. Cannabinoids in the management of difficult to treat pain. Therapeutics and Clinical Risk Management. 2008;4: Sativex [product monograph]. Salisbury, Wiltshire: GW Pharma Ltd; Schoedel KA, Chen N, Hilliard A, et al. A randomized, double-blind, placebo-controlled, crossover study to evaluate the subjective abuse potential and cognitive effects of nabiximols oromucosal spray in subjects with a history of recreational cannabis use. 18. Stott C, White L, Wright S. A phase I, open-label, randomized, crossover study in three parallel groups to evaluate the effect of rifampicin, ketoconazole, and omeprazole on the pharmacokinetics of THC/CBD oromucosal spray in healthy volunteers. Springerplus. 2013;2: Stott CG, Wright S, Guy GW. A comparison of pharmacokinetic profiles of inhaled delta-9-tetrahydrocannabinol (THC) from smoked cannabis with Sativex oromucosal spray in humans: implications for possible symptomatic treatment in multiple sclerosis. Eur J Neurol. 2008;15: Ternel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small cell lung cancer. N Engl J Med. 2010;363: World Health Organization. Cancer pain relief (Second edition) Accessed November 1, Available at: Bornheim LM, Kim KY, Li J, et al. Effect of cannabidiol pretreatment on the kinetics of tetrahydrocannbinol metabolites in mouse brain. Drug Metab Dispos. 1995;23: Millns PJ, Chapman V, Kendall DA. Cannabinoid inhibition of the capsaicin-induced calcium response in rat dorsal root ganglion neurons. Br J Pharmacol. 2001;132: Ward SJ, McAllister SD, Neelakantan H, et al. Cannabidiol inhibits paclitaxel-induced neuropathic pain through 5-HT 1A receptors without diminishing nervous system function or chemotherapy efficacy. [Published online ahead of print]. Br J Pharmacol DOI: /bph Basto 16

17 Appendix A. Abbreviation Key AE adverse effects ARCI Addiction Research Center Inventory BPI-SF Brief Pain Inventory Short Form ECS endocannabinoid system EORTC European Organization for Research of Treatment for Cancer CB 1 cannabinoid receptor 1 CB 2 cannabinoid receptor 2 CBD cannabidiol CRT - Choice Reaction Time DAT Divided Attention Test FDA Food and Drug Administration MADRS Montgomery Asberg Depression Rating Scale NCCN National Comprehensive Cancer Network NRS Numerical Rating Scale PAC-QoL Patient Assessment of Constipation Quality of Life Questionnaire RCT Randomized, controlled trial STM Sternberg Short Term Memory THC - delta-9-tetrahydrocannabinol TRPV1 transient receptor potential cation channel subfamily V member 1 (aka vanilloid receptor type 1) VAS Visual Analogue Scale WHO World Health Organization Appendix B. Opioid comparison table Drug IV:PO Duration of Action Morphine Clinical considerations (hrs) Equivalency Morphine 1: mg Caution in renal impairment Hydromorphone 1: mg Caution in renal impairment Fentanyl No PO mg (IV), 0.2 Preferred agent in renal impairment mg (TD) Methadone 1:2 3-6 Varies Oral conversion ratio varies between patients Can accumulate, closer follow-up required Oxycodone No IV mg Hydrocodone No IV mg Only available in combination with APAP or ibuprofen Oxymorphone 1: mg Codeine No IV mg Caution in renal impairment Ineffective in 10-30% of patients who are unable to metabolize into morphine Not recommended for cancer pain: meperidine, mixed agonist-antagonists (pentazocine, anlbuphine, butorphanol) Basto 17

18 Appendix C. Measures used in studies Abbreviation Measure Description ARCI Addiction Research Center Inventory 550-item inventory to assess subjective drug effects and personality characteristics for substances with abuse potential: morphine, pentobarbital, chlorpromazine, LSD, amphetamine, pyrahexyl, alcohol BPI-SF Brief Pain Inventory- Short Form Severity of pain, average and worst pain, amount that pain interferes with daily life CRT Choice Reaction Time Tests psychomotor speed using numeric keypad DAT Divided Attention Test Manual tracking and visual target detection task subjects maintain image of airplane over randomly curving road while responding to randomly presented visual targets EORTC QLQ-C30 The European Organization for Research and Treatment of Cancer - Quality of Life Questionnaire PAC-QoL MADRS Patient Assessment of Constipation Quality of Life Questionnaire Montgomery-Asberg Depression Rating Scale Assessment of quality of life of cancer patients Functional status (6): global health status, physical functioning, role functioning, emotional functioning, cognitive functioning, social functioning Adverse symptoms (8): fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea Financial difficulties Assesses the burden of constipation on everyday functioning and well-being Ten-item diagnostic questionnaire to measure severity of depressive eepisodes in patients with mood disorders NRS Numerical Rating Scale 11-point scale (0-10) for reporting pain STM Sternberg Short-term Memory Test of short-term storage capacity and working memory VAS Visual Analogue Scale Measurement instrument for subjective characteristics or attitudes that cannot be directly measured Basto 18

19 Appendix D. Additional literature on nabiximols use in other indications AUTHORS TITLE Spasticity in multiple sclerosis Serpell MG, Notcutt W, Collin C. Sativex long-term use: an open-label trial in patients with spasticity due to multiple sclerosis Notcutt W, Lnagford R, Davies P, A placebo-controlled, parallel-group, randomized et al. withdrawal study of subjects with symptoms of spasticity due to multiple sclerosis who are receiving long term Sativex (nabiximols) Novotna A, Mares J, Ratcliffe S, et al. Collin C, Ehler E, Waberzinek G, et al. A randomized, double-blind, placebo-controlled, parallel-group, enriched design study of nabiximols, as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasiticity due to multiple sclerosis Wade DT, Collin C, Stott C, et al. Meta-analysis of the efficacy and safety of Sativex (nabiximols), on spasticity in people with multiple sclerosis Neuropathic pain in multiple sclerosis Langford RM, 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 Allodynia and chemotherapy-induced neuropathic pain Lynch ME, Cesar-Rittenberg P, A double-blind, placebo-controlled, crossover pilot trial Hohmann AG with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain NurmikkoTJ, Serpell MG, Hoggart B, et al. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial Basto 19