TITLE: Cannabinoids as Co-Analgesics: Review of Clinical Effectiveness DATE: 23 July 2010 CONTEXT AND POLICY ISSUES: For centuries cannabis has been used for pain relief.1,2 Cannabinoids are the compounds of cannabis that produce therapeutic as well as psychotropic effects.3 Available cannabinoid drugs include delta nine-tetrahydrocannabinol (Δ-9-THC), dronabinol (a synthetic Δ-9-THC), nabilone, and a combination of synthetic Δ-9-THC and cannabidiol (THC/CBD; Sativex).4 Sativex was approved by Health Canada in 2005 for use as an adjunctive treatment for neuropathic pain for multiple sclerosis patients.4,5 Nabilone (Cesamet) is approved for treatment and management of severe nausea and vomiting induced by chemotherapy,4 but there is clinical evidence supporting its use for pain management.6,7 Studies investigating clinical utility of cannabinoids in the management of pain show conflicting evidence. While the results of studies investigating therapeutic benefits of cannabinoids in neuropathic pain are promising,8-11 the effectiveness of cannabinoids in the management of other types pain is unclear.11-15 Some evidence suggests that cannabinoids are as effective as placebo for treating pain and in some cases may be anti-analgesic when administered at high doses.12,13,15-17 In light of limited evidence supporting clinical use of cannabis in the management of pain, a recent systematic review of published English studies on clinical effectiveness of nabilone in the treatment of chemotherapy-induced nausea and vomiting and pain15 concluded that “nabilone is disappointing when used to manage acute pain”15 and that “cannabinoids have little evidence of benefit in the management of cancer pain.”15 The most recent review of clinical studies on the effectiveness of cannabinoids in pain and other therapeutic indications13 concluded that “as efficacy and tolerability of these agents remain questionable, it is important that cannabinoids not be considered ‘first-line’ therapies for conditions for which there are more supported and better-tolerated agents. Instead, these agents could be considered in a situation of treatment failure with standard therapies or as adjunctive agents where appropriate.”13 The present report reviews the current evidence for the clinical effectiveness of cannabinoids as co-analgesics for

Disclaimer: The Health Technology Inquiry Service (HTIS) is an information service for those involved in planning and providing health care in Canada. HTIS responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. HTIS responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners’ own terms and conditions.

non-neuropathic pain. The use of cannabinoids for the treatment of neuropathic pain is discussed in another health technology inquiry service rapid report.18 RESEARCH QUESTION: What is the clinical effectiveness of cannabinoids as co-analgesics for the treatment of nonneuropathic pain? METHODS: A limited literature search was conducted on key health technology assessment resources, including PubMed, Embase, the Cochrane Library (Issue 6, 2010), University of York Centre for Reviews and Dissemination (CRD) databases, EuroScan, international health technology agencies, and a focused Internet search. The search was limited to English language articles published between Jan 1, 2005 and Jun 17, 2010. Filters were applied to limit the retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, non-randomized studies, and guidelines. Internet links were provided, where available. SUMMARY OF FINDINGS: Relevant health technology assessments, systematic reviews, and meta-analyses were not identified. Three randomized controlled trials3,19,20 and one observational study21 were identified. No relevant guidelines were identified. Studies were included that investigated clinical effectiveness of cannabinoids administered in combination with another analgesic for the treatment of patients with non-neuropathic pain. Randomized controlled trials Three relevant randomized controlled trials (RCTs)3,19,20 were identified. A summary of the characteristics and results of the studies are presented in Appendix 1. Johnson et al, 201019 compared the efficacy of THC/CBD (Sativex), THC extract, and placebo in cancer patients who responded to opioid treatment sub-optimally (n = 177), with baseline pain severity score of 4 or above on a 0 (no pain) to 10 (worst pain) numerical rating scale (NRS). Efficacy was measured as a change from baseline in NRS pain score and use of breakthrough medication. The trial ran for a period of two weeks. In addition to standard opioid dose, 60 patients randomly received THC/CBD oromucosal spray delivering 2.7 mg of THC and 2.5 mg of CBD per actuation (maximum eight actuations every three hours up to a maximum of 48 actuations per 24 hours), 58 patients received 2.7 mg THC extract, and 59 patients received placebo. The results (detailed in Table1) showed that mean treatment difference, adjusted for the placebo response, was statistically significant for reduction in pain for patients receiving THC/CBD adjunctive treatment, but was not significant for the patients receiving THC adjunctive treatment. There were more patients in THC/CBD group who experienced more than 30% pain reduction from baseline compared with both the THC group and the placebo group. A similar number of patients with more than 30% pain reduction from baseline was reported in the THC and placebo groups. The authors observed “no change from baseline in median dose of opioid background medication or mean number of doses of breakthrough medication across treatment groups.”19 Mild to moderate severity adverse events (somnolence, dizziness, and nausea)

Cannabinoids as Co-Analgesics 2

related to treatment were reported in 106 (60%) patients (treatment groups of patients with adverse events not reported). The study concluded that THC/CBD is useful adjunctive pain relief therapy in advanced cancer patients experiencing inadequate analgesia despite the use of opioid therapy. Table 1: Results from Johnson et al, 201019 Outcome Mean treatment difference (adjusted for placebo) for pain reduction Percentage of patients with > 30% reduction in pain

THC/CBD 0.67 (p = 0.014) 43%

THC 0.32 p = 0.245) 23%

Placebo N/A 21%

N/A = not applicable

Narang et al, 200820 examined the efficacy of dronabinol (a synthetic Δ-9-THC) in patients (n= 30) experiencing moderate to severe chronic non-cancer pain (at least 4 on a 0 to 10 NRS) while on stable doses of opioids. The trial consisted two phases. The first phase (n = 30) was a one-week single-dose double-blinded randomized placebo-controlled study in which each subject received placebo, 10 mg, or 20 mg dronabinol capsules in addition to his/her stable dose of opioid (not specified). The second phase (n = 28) was a 4-week period extension of the first phase in which patients taking stable opioid doses entered a stepwise dosage schedule of dronabinol starting as little as 5 mg twice a day and as much as 20 mg three times a day (there was no control group in this phase). For the first phase, the outcome was measured in terms of total pain relief (TOTPAR) score at 8 hours (higher score indicating more pain relief) and pain intensity difference (SPID) score for 8 hours after receiving the test drug. For the second phase, the outcome was expressed in terms of change in pain intensity from baseline using NRS pain score. Patient satisfaction points (through questionnaires) and adverse events were secondary outcomes in both phases. In the first phase, the results (Table 2A) showed that pain relief (TOTPAR) for patients receiving dronabinol was statistically significantly greater compared with placebo. Similarly, compared to placebo, a significant decrease in pain intensity (SPID) was observed for patients taking dronabinol 10 mg and 20 mg. Patient satisfaction was greater for both dronabinol groups compared with the placebo group. In the second phase of the study (Table 2B), a statistically significant decrease in biweekly average pain score was observed. Also, pain relief scores and patient satisfaction points increased by 1.7 and 1.8, respectively. In both phases, dry mouth, drowsiness, sleepiness, and dizziness were frequently reported adverse events that increased as dronabinol dose increased. Table 2A: First Phase Results from Narang et al, 200820 Outcome Dronabinol 10mg Dronabinol 20mg TOTPAR 39.7 (p = 0.05) 41.7 (p = 0.01) SPID -17.4 (p = 0.01) -19.7 (p = 0.01) Patient satisfaction 5.9 (p = 0.05) 5.9 (p = 0.05)

Placebo 31.1 -6.4 3.9

TOTPAR =total pain relief; SPID = pain intensity difference

Cannabinoids as Co-Analgesics 3

Table 2B: Second Phase Results from Narang et al 200820 Average biweekly pain reduction Mean value Baseline versus week 2 ≈ -1.00 Week 1 versus week 3 ≈ -0.9 Week 2 versus week 4 ≈ -0.9

Reported P value 0.01 0.05 0.05

≈ Approximate; extrapolated from results graph

The study concluded that “overall, the use of dronabinol was found to result in additional analgesia among patients taking opioids for chronic non-cancer pain.”20 As noted by the authors, this study was limited in that it is difficult to attribute observed pain reduction to dronabinol alone due to the lack of control arm in the open-label second phase. Also, the results of the study may be questionable due to its limited number of patients and heterogeneity in the causes of pain and opioid dosage. Blake et al, 20063 compared the efficacy of THC/CBD (Sativex) with placebo in 58 patients experiencing pain caused by rheumatoid arthritis that is not adequately controlled by nonsteroidal anti-inflammatory drugs (NSAID) and prednisolone therapy. In this 5-week trial, THC/CBD oromucosal spray delivering 2.7 mg of THC and 2.5 mg of CBD per actuation was administered in the evenings according to patient response (maximum six actuations every two days). Thirty-one patients received THC/CBD and 27 patients received placebo. Stable doses of NSAID and prednisolone were maintained throughout the trial period in both groups. The primary outcome was pain on movement measured using NRS each morning during the 5week trial period. The average pain score of the last 4 days of 14-day baseline period was used as a baseline score. Secondary outcomes included pain at rest as measured by NRS, sleep quality, short form McGill Pain questionnaire (SF-MPQ), and the 28-joint disease activity score (DAS28). The results showed a statistically significant improvement compared to placebo in pain on movement, pain at rest, quality of sleep, DAS28, and the SF-MPQ in the THC/CBD group (Table 3). In the THC/CBD group, mild or moderate adverse events (AEs) were observed in 8 patients (26%), with no withdrawal due to AEs. There were three (11%) patients who withdrew due to AEs in the placebo group. Severe AEs occurred in two patients (6%) in the THC/CBC group and six patients (22%) in the placebo group. There were no serious AEs in the THC/CBD group, and two in the placebo group. Descriptions of serious and severe AEs were not reported in the study. Table 3: Results from Blake et al, 20063 Outcome compared with placebo Mean value Average reduction in pain on movement Average reduction in pain at rest Average quality of sleep Average DAS28 SF-MPQ, average pain at present

-0.95 -1.04 -1.17 -0.76 -0.72

95% confidence interval -1.83, -0.02 -1.90, -0.18 -2.20, -0.14 -1.23, -0.28 -1.30, -0.14

Reported P value 0.044 0.018 0.027 0.002 0.016

DAS28 = 28-joint disease activity score; SF-MPQ = short form McGill Pain questionnaire (SF-MPQ)

Cannabinoids as Co-Analgesics 4

The authors concluded that THC/CBD produced a significant analgesic effect and disease activity suppression. Limitations to this study included the use of average baseline pain score in the last 4 days of baseline period in comparison to average pain score of the last 14 days of treatment; this may negate the conventional measurement of pain relief that requires analgesia to produce more than 30% reduction in pain in order to be considered effective. The Blake et al, 20063 study neither provides percentage reduction in pain nor percentage of patients experiencing more than 30% reduction in pain. Observational studies One relevant observational study by Phan NQ et al, 201021 was identified. The study was an open-labeled trial in 8 patients (2 women, 6 men, mean 56 years old) with acute postherpetic neuralgia (PHN) for at least one month after initial skin changes (n = 4) and chronic PHN (for at least 4 months after initial skin changes; n =4) after herpes zoster affecting the face. Three patients out of 8 maintained systemic analgesia (tramadol, paracetamol, or gabapentin) during the trial. Cream (PEA, Physiogel Al Creme®) containing a cannabinoid receptor agonist was applied twice a day for two to four weeks to the affected site. The primary outcome was pain intensity as measured by visual analogy scale (VAS) from 0 (no pain) to 10 (worst pain imaginable). The results showed that 5 out of 8 patients (about 63%) had significant pain reduction (4.75 baseline VAS to 1.00 after 2 to 4 week treatment; p = 0.008). While patients with acute PHN responded well to Physiogel Al Cream (about 89% pain reduction), three patients (37.5%) with chronic PHN had less than 17% pain reduction. No adverse events were observed. The authors concluded that topical cannabinoid receptor agonists are an effective and welltolerated adjuvant therapy option in PHN. Limitations Health technology assessments or systematic reviews on the use of cannabinoids as coanalgesics in non-neuropathic pain management were not identified. Three RCTs and one observational study were identified and reviewed. In the reviewed RCTs, the use of cannabinoids as an adjuvant therapy for management of pain, though supported, has not been well studied, particularly with respect to dosage of co-analgesics, patient population, and use of pain measurement tools. For instance, in the Johnson et al, 201019 study, daily average oral dose for morphine equivalent varied across the three trial arms (THC/CBD, THC, and placebo). Variation in existing treatment regimes may have affected results and generalizability of the Johnson et al, 201019 study. Similarly, interpretation and validity of the results of the Narang et al, 200820 study is limited due to limited number of subjects (30 patients) and the inclusion of a heterogeneous pain patient population on various opioid doses. The RCT by Blake et al, 20063 neither provides percentage reduction in pain nor percentage of patients experiencing more than 30% reduction in pain, and therefore it is difficult to interpret the results. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING: In conclusion, the four identified studies suggest that the use of cannabinoids as co-analgesia in patients with non-neuropathic pain is effective. The patient populations included in the studies varied and included patients with cancer pain, non-cancer pain, rheumatoid arthritis, and acute postherpetic neuralgia. The studies also varied with type of cannabinoid used, the agents used for co-analgesia, and the outcome measurements. The information is limited, and therefore

Cannabinoids as Co-Analgesics 5

uncertainty exists with regards to efficacy and adverse events, ideal patient population, dosage, and formulation which may be a consideration for decision-making. Research into a better understanding of patient populations which may benefit the most from an adjuvant cannabinoid and the required dosage combination for co-analgesics considering their adverse-event profile may be needed to inform decision-making.

PREPARED BY: Health Technology Inquiry Service Email: [email protected] Tel: 1-866-898-8439

Cannabinoids as Co-Analgesics 6

REFERENCES: 1.

Mather L. Cannabinoid pharmacotherapy: past, present and future. Minerva Anestesiol. 2005 Jul;71(7-8):405-12.

2.

Gofeld M, Robinson S, Faclier G. Administration of nabilone for postoperative pain control in the marijuana-addicted: Case study. Acute Pain. 2006;8(1):29-32.

3.

Blake DR, Robson P, Ho M, Jubb RW, McCabe CS. Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology (Oxford) [Internet]. 2006 Jan [cited 2010 Jun 28];45(1):50-2. Available from: http://rheumatology.oxfordjournals.org/cgi/reprint/45/1/50

4.

Namaka M, Leong C, Grossberndt A, Klowak M, Turcotte D, Esfahani F, et al. A treatment algorithm for neuropathic pain: an update. Consult Pharm. 2009 Dec;24(12):885-902.

5.

Rog DJ, Nurmikko TJ, Young CA. Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial. Clin Ther. 2007 Sep;29(9):2068-79.

6.

Burns TL, Ineck JR. Cannabinoid analgesia as a potential new therapeutic option in the treatment of chronic pain. Ann Pharmacother. 2006 Feb;40(2):251-60.

7.

Maida V, Ennis M, Irani S, Corbo M, Dolzhykov M. Adjunctive nabilone in cancer pain and symptom management: a prospective observational study using propensity scoring. J Support Oncol [Internet]. 2008 Mar [cited 2010 Jun 30];6(3):119-24. Available from: http://www.supportiveoncology.net/journal/articles/0603119.pdf

8.

Barnes MP. Sativex: clinical efficacy and tolerability in the treatment of symptoms of multiple sclerosis and neuropathic pain. Expert Opin Pharmacother. 2006 Apr;7(5):607-15.

9.

Salim K, Schneider U, Burstein S, Hoy L, Karst M. Pain measurements and side effect profile of the novel cannabinoid ajulemic acid. Neuropharmacology. 2005 Jun;48(8):116471.

10.

Wilsey B, Marcotte T, Tsodikov A, Millman J, Bentley H, Gouaux B, et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain. 2008 Jun;9(6):506-21.

11.

Ashton JC, Milligan ED. Cannabinoids for the treatment of neuropathic pain: clinical evidence. Curr Opin Investig Drugs. 2008 Jan;9(1):65-75.

12.

Guindon J, Walczak JS, Beaulieu P. Recent advances in the pharmacological management of pain. Drugs. 2007;67(15):2121-33.

13.

Turcotte D, Le Dorze JA, Esfahani F, Frost E, Gomori A, Namaka M. Examining the roles of cannabinoids in pain and other therapeutic indications: a review. Expert Opin Pharmacother. 2010 Jan;11(1):17-31.

Cannabinoids as Co-Analgesics 7

14.

Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, et al. Cannabis in painful HIVassociated sensory neuropathy: a randomized placebo-controlled trial. Neurology. 2007 Feb 13;68(7):515-21.

15.

Davis MP. Oral nabilone capsules in the treatment of chemotherapy-induced nausea and vomiting and pain. Expert Opin Invest Drugs. 2008 Jan;17(1):85-95.

16.

Martin-Sanchez E, Furukawa TA, Taylor J, Martin JL. Systematic review and metaanalysis of cannabis treatment for chronic pain. Pain Med. 2009 Nov;10(8):1353-68.

17.

Beaulieu P. Effects of nabilone, a synthetic cannabinoid, on postoperative pain. Can J Anaesth. 2006 Aug;53(8):769-75.

18.

Health Technology Inquiry Service (HTIS). Cannabinoids for the management of neuropathic pain: review of clinical effectiveness [Internet]. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2010. [cited 2010 Jul 19]. Available from: http://www.cadth.ca/media/pdf/l0197_cannabinoids_neuropathic_pain_htis-2.pdf

19.

Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED, Potts R, Fallon MT. 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 Feb;39(2):167-79.

20.

Narang S, Gibson D, Wasan AD, Ross EL, Michna E, Nedeljkovic SS, et al. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. J Pain. 2008 Mar;9(3):254-64.

21.

Phan NQ, Siepmann D, Gralow I, Stander S. Adjuvant topical therapy with a cannabinoid receptor agonist in facial postherpetic neuralgia. J Dtsch Dermatol Ges. 2010 Feb;8(2):8891.

Cannabinoids as Co-Analgesics 8

APPENDIX 1: Study Characteristics and Results of Randomized Controlled Trials Author Johnson et al, 201019

Narang et al, 200820

Study design Multicenter doubleblind, randomized placebo controlled, parallelgroup study

Doubleblinded randomized placebo controlled, single-dose trial (phase I) followed by an openlabeled, multidose extension trial (phase II)

Patient characteristics 177 cancer patients from 28 European centers, ≥ 4 pain score per NRS at baseline

30 patients with chronic noncancer pain from Brighan and Women’s Hospital in Boston, MA, taking stable dose of opioid but experience pain of ≥ 4 score per NRS

Interventions

Comparator

Results

Conclusion

(i) Sativex (THC/CBD) oromucosal spray (2.7 mg THC; 2.5 mg CBD per actuation, maximum 48 actuations/ day) plus opioid medication (average mean 217 mg/day) (ii) 2.5 mg THC extract/ actuation, (maximum 48 actuations/ day) for two week period plus opioid.

Placebo plus opioid medication with average mean dose of 217 mg/day

Statistically significant reduction in pain severity for THC/CBD group (0.67 points per NRS, p= 0.014) and statistically insignificant reduction in pain severity for THC group (0.32 points per NRS, p = 0.245).

The study concluded that THC/CBD is useful adjunctive pain relief therapy in advanced cancer patients experiencing inadequate analgesia despite the use of opioid therapy.

Phase I: Patients received either dronabinol 10 mg or 20 mg, in addition to stable opioid dose (not specified) for duration of one week.

Placebo plus a stable dose opioid (dose not specified)

Phase II: In addition to opioids. patients took 5 mg dronabinol once or twice

Mild to moderate severity somnolence, dizziness, and nausea related to treatment were reported in 106 (60%) out of 177 patients. Phase I: patients in dronabinol group experienced a significant decrease in pain intensity and treatment satisfaction; no different found between 10 mg and 20 mg recipients.

Dronabinol resulted in increased analgesia

Cannabinoids as Co-Analgesics 9

Author

Study design

Patient characteristics

Interventions

Comparator

a day and increased to as much as 20 mg 3 times a day, for duration of four weeks

Blake et al, 20063

Doubleblind, randomized placebo controlled, parallelgroup study

58 patients experiencing pain caused by rheumatoid arthritis, recruited from Royal National Hospital for Rheumatic Disease, UK.

Sativex oromucosal spray delivering 2.7 mg of THC and 2.5 mg of CBD per actuation (maximum six actuations every two days) plus stable doses of NSAID and prednisolone

Results

Conclusion

Phase II: Significant pain relief and treatment satisfaction was observed following dronabinol titration.

Placebo plus stable doses of NSAID and prednisolone (doses not specified)

In both phases dry mouth, drowsiness, sleepiness, and dizziness were frequently reported adverse events that increased as dronabinol dose increased. Mean difference from the baseline for pain on movement was -0.95 (p = 0.044). Mean difference from the baseline for pain at rest was -1.04 (p = 0.018).

Sativex produced significant analgesic effect and disease activity suppression.

Severe AEs in the treatment arm were constipation in two patients (6%)

Cannabinoids as Co-Analgesics 10

Author

Study design

Patient characteristics

Interventions

Comparator

Results

Conclusion

and dizziness in eight patients (26%) AE = adverse event; CBD = cannabidiol; NRS = numerical rating scale; NSAID = non-steroidal anti-inflammatory drug; THC = tetrahydrocannabinol

Cannabinoids as Co-Analgesics 11