- Email: [email protected]
Effect of cannabis on opioid use in patients with cancer receiving palliative care
SCIENCE AND PRACTICE Journal of the American Pharmacists Association xxx (2019) 1e4
Contents lists available at ScienceDirect
Journal of the American Pharmacists Association journal homepage: www.japha.org
RESEARCH NOTES
Effect of cannabis on opioid use in patients with cancer receiving palliative care Elizabeth R. Pritchard, Lindsey Dayer, Jennifer Belz, Brittany Forseth, Sarah E. Harrington, Jacob T. Painter* a r t i c l e i n f o
a b s t r a c t
Article history: Received 27 June 2019 Accepted 28 October 2019
Objective: Opioids are the primary therapy for cancer-related pain in patients receiving palliative care. More states are legalizing medical cannabis, which may provide a pain management alternative for some of these patients. This study aimed to estimate the effect of cannabis on opioid use in patients with cancer receiving palliative care. Methods: This was a retrospective cohort study of patients with cancer at an academic medical center palliative care clinic. The primary outcome was change in morphine equivalent daily dose (MEDD) from baseline to 84-day follow-up in the cannabis plus opioid group compared to that in the opioid-only group. Results: A total of 83 patients were included: 61 in the opioid monotherapy group and 22 in the cannabis plus opioid group. An increase in MEDD from the baseline to 84 days was seen in both the opioid monotherapy and opioid plus cannabis group (28.8 vs. 10.8); however, the study lacked power to detect a statistical difference. Conclusion: A possibly meaningful difference in MEDD increase was seen when comparing the opioid monotherapy group with the opioid plus cannabis group. However, the study was not powered to test this hypothesis; the findings suggest that further research is warranted to determine the impact of cannabis use on opioid dosing in patients receiving palliative care for cancer. © 2019 Published by Elsevier Inc. on behalf of the American Pharmacists Association.
Background Cannabis is a natural compound used for alleviating symptoms in many disease states. Its effects are mainly produced through the actions of the endocannabinoid system. The 2 main active phytochemicals are D9-tetrahydrocannabinol (THC) and cannabidiol (CBD).1 THC is the cannabinoid primarily responsible for psychoactive effects (euphoria or dysphoria) and causes relaxation and has anti-inflammatory effects. CBD does not have psychoactive effects, but it has some anti-inflammatory effects.2 In addition to its antiinflammatory effects, CBD has pain-relieving effects
Disclosure: The authors declare no relevant conflicts of interest or financial relationships. * Correspondence: Jacob T. Painter, PharmD, MBA, PhD, University of Arkansas for Medical Sciences, 4301 W Markham St., Little Rock, AR 72205. E-mail address: [email protected] (J.T. Painter).
mediated by inhibiting prostaglandin synthesis (a hormone produced in response to injury or inflammation) and acts on pain-sensing pathways in the brain.3 When treating patients for cancer-related pain, the primary pain-relieving therapy is opioid medications.4,5 For patients with pain that is not well controlled, alternative or adjunctive therapies, such as cannabis, have been used. The legal status of cannabis varies from state to state; the medical use of cannabis is currently legal in 14 states including Arkansas. The effects of cannabis on pain management have been studied in other populations such as patients with human immunodeficiency virus and those with chronic pain.6-8 This literature suggests that cannabis-based therapies have benefits in managing pain. A study conducted outside of the United States followed oncology patients who received a medical cannabis permit. Sixty-nine of 113 patients reported an improvement in pain management along with overall well-being.9 Another prospective study outside the United States followed more than 3000 patients with various types of cancer receiving medical
https://doi.org/10.1016/j.japh.2019.10.013 1544-3191/© 2019 Published by Elsevier Inc. on behalf of the American Pharmacists Association.
SCIENCE AND PRACTICE E.R. Pritchard et al. / Journal of the American Pharmacists Association xxx (2019) 1e4
cannabis. At a 6-month follow-up survey, pain intensity and quality of life were assessed; only 4.6% reported an intensity of 8-10 (scale, 0-10) compared with 52.9% before treatment initiation, whereas 69.5% reported good quality of life compared with 18.7% who reported good quality of life at the beginning of the study.10 Although an increasing number of states have legalized medical cannabis, evidence on its effectiveness is lacking. Studies have examined the use of medical cannabis in patients with cancer, but evidence supporting the use in patients with cancer receiving palliative care is lacking. Palliative care services aim to decrease patient suffering and to provide the best possible quality of life for patients and their families. Palliative care can include hospice and nonhospice care. Although definitions vary, here, palliative care refers to nonhospice care offered for patients with serious disease or illness and may be given along with life-prolonging or curative treatment.11-13 The purpose of this study was to examine the effect of concurrent opioid and cannabis use when compared with opioid use alone in patients with cancer receiving palliative care.
Methods This retrospective cohort study was performed using data from the palliative care clinic (PCC) at an academic medical center. The pharmacist’s role at this practice site includes helping to monitor the urine drug screen (UDS) of patients in the PCC. In addition, it includes providing a detailed medication reconciliation to help aid in medication safety and choice of medication or dose. The pharmacist provides patient and caregiver education regarding the use of cannabis and opioids. Data were abstracted from the electronic medical records (EMRs) of patients enrolled in the PCC between October 2014 and October 2017. Inclusion criteria were as follows: patients with a diagnosis of cancer seen in the PCC; patients aged 18 years or older; and patients who had a UDS in clinic within 28 days of the initial PCC visit, an opioid prescription listed in the EMR with a valid morphine equivalent daily dose (MEDD) measurement at the initial PCC visit, and a follow-up appointment within 84 days of the initial PCC visit. The UDS used in this project screened for amphetamine, methamphetamine, barbiturates, benzodiazepines, THC, cocaine, methadone, opiates, and phencyclidine (PCP). Patients with a positive UDS for illicit substances, defined as amphetamine or methamphetamine (unless patients had current prescription for a central nervous system stimulant), barbiturates, cocaine, or PCP, and patients on dronabinol or nabilone therapy were excluded. In addition, patients who received any of the following medications during the study period, as determined by review of the EMR, were excluded: codeine, tramadol, tapentadol, buprenorphine, or pentazocine. These therapies were excluded owing to their limited use in pain management in the PCC. On the basis of UDS results, patients were assigned to the opioids plus cannabis group or opioid monotherapy group. Baseline characteristics abstracted from the EMR included demographic and medication use characteristics. The exposure of interest for the study was the presence of THC on the 28-day UDS report. Patients positive for THC on UDS were considered to comprise the opioid plus cannabis group, whereas those with a THC-free, 28-day UDS made up the opioid-only group. The primary end point of the study was 2
the change in MEDD between the opioid plus cannabis group and the opioid monotherapy group from the baseline to the 84-day follow-up. MEDD change was calculated by subtracting the patient’s MEDD at the baseline from that at the 84-day follow-up. In addition, the group average MEDD at the baseline, 84-day follow-up, and 180-day follow-up was compared. Total average MEDD was calculated on the basis of conversions provided by the Centers for Disease Control and Prevention.14 In addition, medication use for depression, anxiety, and chemotherapy-induced nausea and vomiting at the baseline and follow-up were recorded. The PCC did not have a sufficient number of patients to support a hypothesis-driven statistical analysis. Descriptive statistics are reported, and test statistics for nonparametric unadjusted comparisons are provided in the tables. This study was approved by the local institutional review board. Results A total of 159 patients were seen in the PCC, and 83 patients met the criteria for inclusion in the final analysis: 61 patients in the opioid monotherapy group and 22 patients in the opioid plus cannabis group. Demographics of both the groups are shown in Table 1. The median age of patients in the opioid plus cannabis group was 48 years and in the opioid monotherapy group was 55 years. For the primary end point (Table 2), the change in MEDD from the baseline to the 84-day follow-up in the opioid monotherapy group was an increase of 28.8 morphine milligram equivalents (MME) with an increase of only 10.8 MME in the opioid plus cannabis group. The total average MEDD was Table 1 Baseline characteristics Variable
Opioid only (n ¼ 61)
Age, mean ± SD, y 55 ± 11.06 Sex Female 23 Male 38 Race White 41 Other 20 No. patients on specific opioid at baseline Morphine IR 11 Morphine ER 20 Oxycodone IR 33 Oxycodone ER 2 Hydromorphone 12 Fentanyl 4 Hydrocodone 4 Methadone 12 Oxymorphone d Other medications at baseline SSRI 4 SNRI 7 TCA 1 Bupropion d Mirtazapine 3 Benzodiazepine 10 MEDD at baseline 119.21 (100.31)
Opioid plus THC (n ¼ 22)
P value
48 ± 12.16
0.014
12 10
0.524 d
16 6
0.633 d
2 3 15 2 3 5 2 5 d
0.498 0.102 0.251 0.285 0.749 0.051 0.653 0.761 d
5 3 2 d 3 5 144.32 (129.19)
0.051 0.720 0.170 d 0.187 0.528 0.57
Abbreviations used: IR, immediate release; ER, extended release; MEDD, morphine equivalent daily dosage; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant; THC, D9-tetrahydrocannabinol.
SCIENCE AND PRACTICE Cannabis effect on opioid use in cancer patients
Table 2 Outcomes Variable Primary outcome, mean ± SD MEDD change from initial visit to 84-day follow-up Secondary outcomes, mean ± SD MEDD change from initial visit to 180-day follow-up MEDD average at 84-day follow-up MEDD average at 180-day follow-up Other medications at 84th day of follow-up SSRI SNRI TCA Bupropion Mirtazapine Benzodiazepine
Opioid only (n ¼ 61)
Opioid plus THC (n ¼ 22)
P value
28.84 ± 90.07
10.80 ± 113.48
0.686
46.24 ± 151.66 148.06 ± 128.03 165.58 ± 162.30
99.61 ± 149.45 155.11 ± 136.07 232.84 ± 199.87
0.353 0.955 0.328
4 1 3 d 1 9
4 0 2 d 1 2
0.199 1.00 0.605 d 0.695 0.719
Abbreviations used: MEDD, morphine equivalent daily dosage; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant.
lower overall in the opioid monotherapy group than that in the opioid plus cannabis group at baseline (119.2 vs. 144.3). Increase in MEDD from baseline to the 180-day follow-up was 46.2 MME in the opioid monotherapy group (n ¼ 31) and 99.6 MME in the opioid plus cannabis group (n ¼ 13). No clear changes were observed for the groups between baseline and follow-up for adjuvant medication. Discussion This retrospective cohort study saw an MEDD increase of approximately 25% from baseline to the 84-day follow-up in the opioid monotherapy group and an increase of only 7.5% in the opioid plus cannabis group. Although this estimated difference had a high level of uncertainty, if the observed difference was to hold in a larger study, it would be clinically meaningful. The observed difference in MEDD change may be due to cannabis providing pain relief by suppressing neurotransmitter release and mechanisms causing neuropathic pain15; however, there was no indication in the data as to whether the pain experienced by the patient was neuropathic in nature. It must be noted that the average baseline MEDD was higher in the opioid plus cannabis group. Moreover, the effect of differences in prescriber behavior as a result of patient-level variation not observed in this study cannot be ruled outdfor example, patients who test positive for THC may exhibit behaviors that prescribers see as risky, and thus, opioid prescriptions do not increase at the same rate. There are several limitations to this study, including the retrospective nature of data analysis and the sample size. In addition, at the 180-day follow-up, many patients could not be analyzed because they did not arrive for their follow-up appointments, were transitioned into hospice care and were no longer followed at the PCC, or died. Other study limitations include how patients were assigned into treatment groups on the basis of UDS. Any patient who had a UDS that was positive for THC at 28 days was sorted into the opioid plus cannabis group. From these data, it is not possible to determine how often patients used cannabis and how it influenced opioid use or to make an assertion regarding exposure to cannabidiol, which may affect pain relief. It is possible that patients who tested positive at the inclusion point of our study were no longer using cannabis at follow-up. In addition, we were not
able to correlate changes with possible disease progression or other life events that may affect their scoring. Studying cannabis has many inherent limitations. The amount, type, and frequency of its use are usually unknown. Cannabis is currently a schedule I substance per the U.S. Drug Enforcement Agency,16 making it difficult to perform clinical research. The investigators chose to study cannabis because many patients in the PCC use cannabis or have reported use in the past. Conclusion In conclusion, this retrospective cohort study examining patients with cancer receiving palliative care saw a difference with the increase in MEDD between baseline and follow-up and between patients treated with opioids alone and those who were concurrently using opioids and cannabis; however, the study was not adequately powered to detect an effect with precision. A larger, more robust study could test this hypothesis while controlling for potential confounding factors due to differences in baseline patient characteristics. Acknowledgments The authors thank the Arkansas Clinical Data Repository (AR-CDR) for providing assistance in data collection. Data for the study were provided by AR-CDR maintained by the Department of Biomedical Informatics of the College of Medicine at the University of Arkansas for Medical Sciences (UAMS). AR-CDR is approved to operate as an enterprise data resource to support research across UAMS. Data in AR-CDR come from the UAMS Electronic Medical Record, tumor registry, billing, and cancer genomic data and comprises encounters since January 5, 2014. References 1. Kramer JL. Medical marijuana for cancer. CA Cancer J Clin. 2015;65(2): 109e122. _ 2. Dzierzanowski T. Prospects for the use of cannabinoids in oncology and palliative care practice: a review of the evidence. Cancers (Basel). 2019;11(2):129. 3. Borgelt LM, Franson KL, Nussbaum AM, Wang GS. The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy. 2013;33(2): 195e209.
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4. Paice JA, Portenoy R, Lacchetti C, et al. Management of chronic pain in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016;34(27):3325e3345. 5. Adult Cancer Pain. NCCN Clinical Practice Guidelines in Oncology. Available at: https://www.nccn.org/professionals/physician_gls/pdf/pain. pdf. Published 2019. Updated 2019. Accessed June 27, 2019. 6. Jensen B, Chen J, Furnish T, Wallace M. Medical marijuana and chronic pain: a review of basic science and clinical evidence. Curr Pain Headache Rep. 2015;19(10):50. 7. Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology. 2009;34(3):672e680. 8. Ware MA, Wang T, Shapiro S, Collet JP, COMPASS study team. Cannabis for the management of pain: assessment of safety study (COMPASS). J Pain. 2015;16(12):1233e1242. 9. Waissengrin B, Urban D, Leshem Y, Garty M, Wolf I. Patterns of use of medical cannabis among Israeli cancer patients: a single institution experience. J Pain Symptom Manage. 2015;49(2):223e230. 10. Bar-Lev Schleider L, Mechoulam R, Lederman V, et al. Prospective analysis of safety and efficacy of medical cannabis in large unselected population of patients with cancer. Eur J Intern Med. 2018;49(3):37e43. 11. Kelley AS, Meier DE. Palliative care–a shifting paradigm. N Engl J Med. 2010;363(8):781e782. 12. Fadul N, Elsayem A, Palmer JL, et al. Supportive versus palliative care: what's in a name? A survey of medical oncologists and midlevel providers at a comprehensive cancer center. Cancer. 2009;115(9): 2013e2021. 13. Dayer LE, McDade ER, Harrington S. Pharmacist-delivered patient care in an interdisciplinary team-based institutional palliative care clinic, 2012
4
to 2018. J Palliat Care. 2019, 825859719869614. https://doi.org/10.1016/j. japh.2019.10.013. 14. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain - United States, 2016. MMWR Recomm Rep. 2016;65(1): 1e49. 15. Russo EB, Hohmann AG. Role of cannabinoids in pain management. In: Deer TR, Leong MS, Buvanendran A, Gordin V, Kim PS, Panchal SJ, Ray AL, eds. Comprehensive Treatment of Chronic Pain by Medical, Interventional, and Integrative Approaches. Berlin: Springer; 2013:181e197. 16. U.S. Department of Justice. Title 21 United States Code (USC) Controlled Substances Act: Section 812. Available at: https://www.deadiversion. usdoj.gov/21cfr/21usc/812.htm. Accessed June 27, 2019.
Elizabeth R. Pritchard, Pharm D, BCOP, Associate Professor, College of Pharmacy, University of Tennessee Medical Center, Knoxville, TN Lindsey Dayer, Pharm D, BCACP, Associate Professor, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR Jennifer Belz, BS, Student Pharmacist, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR Brittany Forseth, BS, Student Pharmacist, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR Sarah E. Harrington, MD, FAAHPM, Associate Professor, College of Medicine, Division of Palliative Medicine Department of Internal Medicine University of Arkansas for Medical Sciences College of Medicine, Little Rock, AR Jacob T. Painter, PharmD, MBA, PhD, Associate Professor, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR
Contents lists available at ScienceDirect
Journal of the American Pharmacists Association journal homepage: www.japha.org
RESEARCH NOTES
Effect of cannabis on opioid use in patients with cancer receiving palliative care Elizabeth R. Pritchard, Lindsey Dayer, Jennifer Belz, Brittany Forseth, Sarah E. Harrington, Jacob T. Painter* a r t i c l e i n f o
a b s t r a c t
Article history: Received 27 June 2019 Accepted 28 October 2019
Objective: Opioids are the primary therapy for cancer-related pain in patients receiving palliative care. More states are legalizing medical cannabis, which may provide a pain management alternative for some of these patients. This study aimed to estimate the effect of cannabis on opioid use in patients with cancer receiving palliative care. Methods: This was a retrospective cohort study of patients with cancer at an academic medical center palliative care clinic. The primary outcome was change in morphine equivalent daily dose (MEDD) from baseline to 84-day follow-up in the cannabis plus opioid group compared to that in the opioid-only group. Results: A total of 83 patients were included: 61 in the opioid monotherapy group and 22 in the cannabis plus opioid group. An increase in MEDD from the baseline to 84 days was seen in both the opioid monotherapy and opioid plus cannabis group (28.8 vs. 10.8); however, the study lacked power to detect a statistical difference. Conclusion: A possibly meaningful difference in MEDD increase was seen when comparing the opioid monotherapy group with the opioid plus cannabis group. However, the study was not powered to test this hypothesis; the findings suggest that further research is warranted to determine the impact of cannabis use on opioid dosing in patients receiving palliative care for cancer. © 2019 Published by Elsevier Inc. on behalf of the American Pharmacists Association.
Background Cannabis is a natural compound used for alleviating symptoms in many disease states. Its effects are mainly produced through the actions of the endocannabinoid system. The 2 main active phytochemicals are D9-tetrahydrocannabinol (THC) and cannabidiol (CBD).1 THC is the cannabinoid primarily responsible for psychoactive effects (euphoria or dysphoria) and causes relaxation and has anti-inflammatory effects. CBD does not have psychoactive effects, but it has some anti-inflammatory effects.2 In addition to its antiinflammatory effects, CBD has pain-relieving effects
Disclosure: The authors declare no relevant conflicts of interest or financial relationships. * Correspondence: Jacob T. Painter, PharmD, MBA, PhD, University of Arkansas for Medical Sciences, 4301 W Markham St., Little Rock, AR 72205. E-mail address: [email protected] (J.T. Painter).
mediated by inhibiting prostaglandin synthesis (a hormone produced in response to injury or inflammation) and acts on pain-sensing pathways in the brain.3 When treating patients for cancer-related pain, the primary pain-relieving therapy is opioid medications.4,5 For patients with pain that is not well controlled, alternative or adjunctive therapies, such as cannabis, have been used. The legal status of cannabis varies from state to state; the medical use of cannabis is currently legal in 14 states including Arkansas. The effects of cannabis on pain management have been studied in other populations such as patients with human immunodeficiency virus and those with chronic pain.6-8 This literature suggests that cannabis-based therapies have benefits in managing pain. A study conducted outside of the United States followed oncology patients who received a medical cannabis permit. Sixty-nine of 113 patients reported an improvement in pain management along with overall well-being.9 Another prospective study outside the United States followed more than 3000 patients with various types of cancer receiving medical
https://doi.org/10.1016/j.japh.2019.10.013 1544-3191/© 2019 Published by Elsevier Inc. on behalf of the American Pharmacists Association.
SCIENCE AND PRACTICE E.R. Pritchard et al. / Journal of the American Pharmacists Association xxx (2019) 1e4
cannabis. At a 6-month follow-up survey, pain intensity and quality of life were assessed; only 4.6% reported an intensity of 8-10 (scale, 0-10) compared with 52.9% before treatment initiation, whereas 69.5% reported good quality of life compared with 18.7% who reported good quality of life at the beginning of the study.10 Although an increasing number of states have legalized medical cannabis, evidence on its effectiveness is lacking. Studies have examined the use of medical cannabis in patients with cancer, but evidence supporting the use in patients with cancer receiving palliative care is lacking. Palliative care services aim to decrease patient suffering and to provide the best possible quality of life for patients and their families. Palliative care can include hospice and nonhospice care. Although definitions vary, here, palliative care refers to nonhospice care offered for patients with serious disease or illness and may be given along with life-prolonging or curative treatment.11-13 The purpose of this study was to examine the effect of concurrent opioid and cannabis use when compared with opioid use alone in patients with cancer receiving palliative care.
Methods This retrospective cohort study was performed using data from the palliative care clinic (PCC) at an academic medical center. The pharmacist’s role at this practice site includes helping to monitor the urine drug screen (UDS) of patients in the PCC. In addition, it includes providing a detailed medication reconciliation to help aid in medication safety and choice of medication or dose. The pharmacist provides patient and caregiver education regarding the use of cannabis and opioids. Data were abstracted from the electronic medical records (EMRs) of patients enrolled in the PCC between October 2014 and October 2017. Inclusion criteria were as follows: patients with a diagnosis of cancer seen in the PCC; patients aged 18 years or older; and patients who had a UDS in clinic within 28 days of the initial PCC visit, an opioid prescription listed in the EMR with a valid morphine equivalent daily dose (MEDD) measurement at the initial PCC visit, and a follow-up appointment within 84 days of the initial PCC visit. The UDS used in this project screened for amphetamine, methamphetamine, barbiturates, benzodiazepines, THC, cocaine, methadone, opiates, and phencyclidine (PCP). Patients with a positive UDS for illicit substances, defined as amphetamine or methamphetamine (unless patients had current prescription for a central nervous system stimulant), barbiturates, cocaine, or PCP, and patients on dronabinol or nabilone therapy were excluded. In addition, patients who received any of the following medications during the study period, as determined by review of the EMR, were excluded: codeine, tramadol, tapentadol, buprenorphine, or pentazocine. These therapies were excluded owing to their limited use in pain management in the PCC. On the basis of UDS results, patients were assigned to the opioids plus cannabis group or opioid monotherapy group. Baseline characteristics abstracted from the EMR included demographic and medication use characteristics. The exposure of interest for the study was the presence of THC on the 28-day UDS report. Patients positive for THC on UDS were considered to comprise the opioid plus cannabis group, whereas those with a THC-free, 28-day UDS made up the opioid-only group. The primary end point of the study was 2
the change in MEDD between the opioid plus cannabis group and the opioid monotherapy group from the baseline to the 84-day follow-up. MEDD change was calculated by subtracting the patient’s MEDD at the baseline from that at the 84-day follow-up. In addition, the group average MEDD at the baseline, 84-day follow-up, and 180-day follow-up was compared. Total average MEDD was calculated on the basis of conversions provided by the Centers for Disease Control and Prevention.14 In addition, medication use for depression, anxiety, and chemotherapy-induced nausea and vomiting at the baseline and follow-up were recorded. The PCC did not have a sufficient number of patients to support a hypothesis-driven statistical analysis. Descriptive statistics are reported, and test statistics for nonparametric unadjusted comparisons are provided in the tables. This study was approved by the local institutional review board. Results A total of 159 patients were seen in the PCC, and 83 patients met the criteria for inclusion in the final analysis: 61 patients in the opioid monotherapy group and 22 patients in the opioid plus cannabis group. Demographics of both the groups are shown in Table 1. The median age of patients in the opioid plus cannabis group was 48 years and in the opioid monotherapy group was 55 years. For the primary end point (Table 2), the change in MEDD from the baseline to the 84-day follow-up in the opioid monotherapy group was an increase of 28.8 morphine milligram equivalents (MME) with an increase of only 10.8 MME in the opioid plus cannabis group. The total average MEDD was Table 1 Baseline characteristics Variable
Opioid only (n ¼ 61)
Age, mean ± SD, y 55 ± 11.06 Sex Female 23 Male 38 Race White 41 Other 20 No. patients on specific opioid at baseline Morphine IR 11 Morphine ER 20 Oxycodone IR 33 Oxycodone ER 2 Hydromorphone 12 Fentanyl 4 Hydrocodone 4 Methadone 12 Oxymorphone d Other medications at baseline SSRI 4 SNRI 7 TCA 1 Bupropion d Mirtazapine 3 Benzodiazepine 10 MEDD at baseline 119.21 (100.31)
Opioid plus THC (n ¼ 22)
P value
48 ± 12.16
0.014
12 10
0.524 d
16 6
0.633 d
2 3 15 2 3 5 2 5 d
0.498 0.102 0.251 0.285 0.749 0.051 0.653 0.761 d
5 3 2 d 3 5 144.32 (129.19)
0.051 0.720 0.170 d 0.187 0.528 0.57
Abbreviations used: IR, immediate release; ER, extended release; MEDD, morphine equivalent daily dosage; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant; THC, D9-tetrahydrocannabinol.
SCIENCE AND PRACTICE Cannabis effect on opioid use in cancer patients
Table 2 Outcomes Variable Primary outcome, mean ± SD MEDD change from initial visit to 84-day follow-up Secondary outcomes, mean ± SD MEDD change from initial visit to 180-day follow-up MEDD average at 84-day follow-up MEDD average at 180-day follow-up Other medications at 84th day of follow-up SSRI SNRI TCA Bupropion Mirtazapine Benzodiazepine
Opioid only (n ¼ 61)
Opioid plus THC (n ¼ 22)
P value
28.84 ± 90.07
10.80 ± 113.48
0.686
46.24 ± 151.66 148.06 ± 128.03 165.58 ± 162.30
99.61 ± 149.45 155.11 ± 136.07 232.84 ± 199.87
0.353 0.955 0.328
4 1 3 d 1 9
4 0 2 d 1 2
0.199 1.00 0.605 d 0.695 0.719
Abbreviations used: MEDD, morphine equivalent daily dosage; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant.
lower overall in the opioid monotherapy group than that in the opioid plus cannabis group at baseline (119.2 vs. 144.3). Increase in MEDD from baseline to the 180-day follow-up was 46.2 MME in the opioid monotherapy group (n ¼ 31) and 99.6 MME in the opioid plus cannabis group (n ¼ 13). No clear changes were observed for the groups between baseline and follow-up for adjuvant medication. Discussion This retrospective cohort study saw an MEDD increase of approximately 25% from baseline to the 84-day follow-up in the opioid monotherapy group and an increase of only 7.5% in the opioid plus cannabis group. Although this estimated difference had a high level of uncertainty, if the observed difference was to hold in a larger study, it would be clinically meaningful. The observed difference in MEDD change may be due to cannabis providing pain relief by suppressing neurotransmitter release and mechanisms causing neuropathic pain15; however, there was no indication in the data as to whether the pain experienced by the patient was neuropathic in nature. It must be noted that the average baseline MEDD was higher in the opioid plus cannabis group. Moreover, the effect of differences in prescriber behavior as a result of patient-level variation not observed in this study cannot be ruled outdfor example, patients who test positive for THC may exhibit behaviors that prescribers see as risky, and thus, opioid prescriptions do not increase at the same rate. There are several limitations to this study, including the retrospective nature of data analysis and the sample size. In addition, at the 180-day follow-up, many patients could not be analyzed because they did not arrive for their follow-up appointments, were transitioned into hospice care and were no longer followed at the PCC, or died. Other study limitations include how patients were assigned into treatment groups on the basis of UDS. Any patient who had a UDS that was positive for THC at 28 days was sorted into the opioid plus cannabis group. From these data, it is not possible to determine how often patients used cannabis and how it influenced opioid use or to make an assertion regarding exposure to cannabidiol, which may affect pain relief. It is possible that patients who tested positive at the inclusion point of our study were no longer using cannabis at follow-up. In addition, we were not
able to correlate changes with possible disease progression or other life events that may affect their scoring. Studying cannabis has many inherent limitations. The amount, type, and frequency of its use are usually unknown. Cannabis is currently a schedule I substance per the U.S. Drug Enforcement Agency,16 making it difficult to perform clinical research. The investigators chose to study cannabis because many patients in the PCC use cannabis or have reported use in the past. Conclusion In conclusion, this retrospective cohort study examining patients with cancer receiving palliative care saw a difference with the increase in MEDD between baseline and follow-up and between patients treated with opioids alone and those who were concurrently using opioids and cannabis; however, the study was not adequately powered to detect an effect with precision. A larger, more robust study could test this hypothesis while controlling for potential confounding factors due to differences in baseline patient characteristics. Acknowledgments The authors thank the Arkansas Clinical Data Repository (AR-CDR) for providing assistance in data collection. Data for the study were provided by AR-CDR maintained by the Department of Biomedical Informatics of the College of Medicine at the University of Arkansas for Medical Sciences (UAMS). AR-CDR is approved to operate as an enterprise data resource to support research across UAMS. Data in AR-CDR come from the UAMS Electronic Medical Record, tumor registry, billing, and cancer genomic data and comprises encounters since January 5, 2014. References 1. Kramer JL. Medical marijuana for cancer. CA Cancer J Clin. 2015;65(2): 109e122. _ 2. Dzierzanowski T. Prospects for the use of cannabinoids in oncology and palliative care practice: a review of the evidence. Cancers (Basel). 2019;11(2):129. 3. Borgelt LM, Franson KL, Nussbaum AM, Wang GS. The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy. 2013;33(2): 195e209.
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Elizabeth R. Pritchard, Pharm D, BCOP, Associate Professor, College of Pharmacy, University of Tennessee Medical Center, Knoxville, TN Lindsey Dayer, Pharm D, BCACP, Associate Professor, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR Jennifer Belz, BS, Student Pharmacist, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR Brittany Forseth, BS, Student Pharmacist, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR Sarah E. Harrington, MD, FAAHPM, Associate Professor, College of Medicine, Division of Palliative Medicine Department of Internal Medicine University of Arkansas for Medical Sciences College of Medicine, Little Rock, AR Jacob T. Painter, PharmD, MBA, PhD, Associate Professor, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR