An Integrated Review of Cannabis and Cannabinoids in Adult Oncologic Pain Management

Review An Integrated Review of Cannabis and Cannabinoids in Adult Oncologic Pain Management

- - - Sarah Shin, BSN, RN, Christine Mitchell, BSN, RN, Kelly Mannion, BSN, RN, Julianne Smolyn, and Salimah H. Meghani, PhD, MBE, RN, FAAN

- ABSTRACT:

Objective: The objective of this paper is to review the available literature regarding the use of cannabis and cannabinoids in adult oncologic pain management. Design and Data Sources: A integrative review was conducted on March 1, 2018 using PubMed, MEDLINE, CINAHL, Em- base, and Scopus. A snowball method was used to extract studies included in systematic reviews that were not included in the primary literature search. Review Method: Articles reviewed address the use of cannabinoids or cannabis for pain management in oncology patients, either as standalone or adjuvant therapy. Results: The final number of articles included is nine articles. Of the nine studies reviewed, eight reviewed the effect of the cannabinoid THC on cancer pain, and one study reviewed the use of medicinally available whole plant cannabis. The following study types were included: multiple multi-center, randomized, placebo- controlled trials and two prospective observational survey studies. Results and Conclusions: Of the eight studies that reviewed the effect of the cannabinoid THC, five found THC to be more From the University of Pennsylvania School of Nursing, Philadelphia, effective than placebo, one found THC to be more effective than pla- Pennsylvania. cebo in American patients but ineffective in patients from other countries, and two found THC to be no more effective than placebo. Address correspondence to Sarah Shin, BSN, RN, University of The study that reviewed the effect of the whole plant cannabis found Pennsylvania, 418 Curie Blvd, that there was a significant decrease in pain among those patients Philadelphia, PA 19104. E-mail: smoking cannabis. Nursing Practice Implications: The lack of evi- [email protected] dence in this field of research suggests a need to change policy sur- Received April 24, 2018; rounding cannabis research. Revised September 12, 2018; Ó 2018 by the American Society for Pain Management Nursing Accepted September 14, 2018.

1524-9042/$36.00 Ó 2018 by the American Society for Pain Management Nursing https://doi.org/10.1016/ j.pmn.2018.09.006

Pain Management Nursing, Vol -,No- (--), 2018: pp 1-12 2 Shin et al.

BACKGROUND AND SIGNIFICANCE inflammation, mechanical invasion of bone or other pain-sensitive structure, or nerve injury. It is severe, Over the past 10 years there have been significant persistent, and often resistant to treatment with opi- changes to laws governing the medical use of cannabis oids (Abrams & Guzman, 2015). Researchers have in the United States and internationally. The U.S. Drug found that certain cannabinoid-1 receptors in the cen- Enforcement Agency currently classifies cannabis, tral nervous system are found in high concentrations in commonly referred to as marijuana or pot, as a areas of the brain that modulate nociceptive process- ‘‘Schedule I controlled substance with no currently ing, with a similar distribution to opioid receptors accepted medical use and a high potential for abuse’’ (Fine & Rosenfeld, 2013). under the Comprehensive Drug Abuse Prevention Despite evolving state policies, the increasing and Control Act of 1970 (United States Drug prevalence of cannabis use, and its implications for Enforcement Administration, n.d.). However, the U.S. potential medical symptom management, the federal Food and Drug Administration has considered how it government’s restrictive policies and regulations might evaluate the scientific rigor of medicinal regarding research into the harms and benefits of cannabis claims, and the review of public data cannabis products have limited research in the United regarding safety and abuse potential is ongoing States. Efforts to determine the value of cannabis or (United States Food and Drug Administration, 2017). cannabinoids for treating medical conditions require Notably, as of March 2018, 30 states and the District researchers to obtain a number of approvals from of Columbia have passed laws that broadly legalize the National Institute on Drug Abuse, the U.S. Food medical cannabis. Eight states and the District of and Drug Administration, the U.S. Drug Enforcement Columbia legalized cannabis for recreational use, and Administration, institutional review boards, offices or some states have decriminalized the possession of departments in state government, state boards of small amounts of cannabis (State Marijuana Laws in medical examiners, and other local agencies 2018 Map, 2018). (National Academies of Sciences, Engineering, and Moreover, a 2017 World Health Organization Medicine; Health and Medicine Division; Board on report found that several countries have modified their Population Health and Public Health Practice; national controls to accommodate cannabidiol as a me- Committee on the Health Effects of Marijuana, dicinal product (Expert Committee on Drug 2017). This has created a gap in the evidence available Dependence, 2017). In addition to these national and for providers and patients to consult while making de- global changes, there has been increasing interest in cisions regarding the use of cannabis and cannabi- the role that cannabis and cannabinoids play in the noids. Stringent federal and local regulations result care of adult patients with cancer among researchers. in the lack of evidence-based information on the po- A 2016 guideline summary on the management of tential pain management applications of cannabis chronic pain in survivors of adult cancers states that and cannabinoids. ‘‘clinicians may follow specific state regulations that The purpose of this paper is to examine clinical allow access to medical cannabis or cannabinoids for studies conducted from 1975-2018 on medical patients with chronic pain after a consideration of cannabis and cannabinoid use for pain management the potential benefits and risks of the available formu- in adult oncology patients. The research question is lations’’ (Paice et al., 2016, p. 3326). as follows: In adult patients with oncologic diseases According to a 2015 National Survey on Drug Use (population) is cannabinoid or cannabis usage (inter- and Health, cannabis is the most popular illicit drug in vention) a beneficial palliative care intervention for the United States, based on past-month users (Center pain management (outcome)? for Behavioral Health Statistics and Quality, 2016). In addition, a 2014 survey found that 89.5% of current adult cannabis users used cannabis for recreational rea- sons and 46.6% of adults used cannabis in part or METHODS entirely for medicinal purposes, with 10.5% of adults A literature search was performed on March 1, 2018 us- solely using cannabis for medicinal purposes ing the following electronic databases: PubMed, MED- (Schauer, King, Bunnell, Promoff, & McAfee, 2016). LINE, CINAHL, Embase, and Scopus. The search used a Patients and providers alike are hopeful that combination of key terms. Additionally, within the cannabis will provide an additional treatment option PubMed and MEDLINE database, MeSH terms were for those who have symptoms uncontrolled by conven- used. For Embase, MeSH terms identified in PubMed tional medications. One particular symptom of interest and MEDLINE were used as key terms without the is pain management. Cancer pain results from MeSH headings. By using MeSH terms where TABLE 1. Table of Evidence

Level of Citation Purpose Design/Method Setting Major Findings Evidence Limitations

1. Noyes, Determine if oral THC Double-blind, randomized University of Significant trend toward 2b: Low- Small sample size limits Brunck, provides an analgesic controlled trial. Patients Iowa Clinical lesser pain with quality power of study. Baram, & effect in patients received one oral dose Research increasing THC doses. RCT Patients only received one Canter, suffering from cancer of either placebo or THC Center Pain relief from 15 and dose of each 1975. pain. Understand the in varying amounts (5, 20 mg THC was medication, limiting dose range where THC 10, 15, 20 mg) at 8:30 significantly higher than understanding of provides pain relief a.m. Patients reported placebo. Pain relief from chronic response to Pain Oncologic Adult in Cannabinoids and Cannabis without toxic side pain and pain relief THC developed slowly medications. effects. hourly. RNs completed and was prolonged. subjective side effect Patients receiving 20 mg observations. THC were heavily sedated, and 15 mg produced drowsiness. Heart rate and blood pressure decreased with 15- and 20-mg doses of THC. 2. Noyes, Estimate the relative Double-blind randomized University of The analgesic effect of 2b: Low- Small sample size limits Brunk, potency of the analgesic controlled trial. Patients Iowa Hospital THC developed slowly quality power of study. Avery, & effects of THC and were admitted to a Clinical and was prolonged. The RCT Patients only received one Canter, codeine. research facility and Research pain reduction dose of each 1975. given a test drug daily at Center experienced with 10 mg medication, limiting 8:30 a.m. Pain THC was roughly understanding of assessments and side equivalent to 120 mg chronic response to effect surveys were codeine and well medications. administered hourly. tolerated. Side effects Patients reported altered RNs completed for 10 mg THC were mild pain response in THC subjective side effect and brief. Side effects (the same pain observations. for 20 mg THC were ‘‘bothered them less’’), more significant, with limiting the patients voicing understanding of THC’s concern. impact on pain. 10 mg THC can be used for Comparison to codeine is relief of mild pain. antiquated—doesn’t provide comparison to more commonly used pain medications. 3. Jochimsen, Assess the effect of Double-blind study. Clinical The 120-mg dose of 2b: Low- Majority of participants Lawton, benzopyranoperidine (a Over the course of the Research codeine was the only quality were women (29/35) VerSteeg, delta-9- study, all 35 patients Center at the dose found to provide RCT with breast or Continued

( ) 3 4

TABLE 1. Continued

Level of Citation Purpose Design/Method Setting Major Findings Evidence Limitations

& tetrahydrocannabinol) received each of the University pain relief that was gynecologic Noyes, on cancer pain and to following on 1 day out of of Iowa clinically signiﬁcant. malignancies, which 1978. compare it with codeine the 5-day evaluation No difference in pain relief make us question and a placebo. period: 2 mg was identiﬁed among whether these results benzopyranoperidine, placebo, 60 mg codeine, are transferrable to other 4mg 2mg types of cancer benzopyranoperidine, benzopyranoperidine, malignancies. 60 mg codeine sulfate, and 4 mg Concludes by saying the 120 mg codeine sulfate, benzopyranoperidine. doses of and 1 placebo dose. The two doses of benzopyranoperidine A nurse observed all 35 benzopyranoperidine examined are not patients and recorded (2 mg, 4 mg) were not as effective at serving as an each patient’s degree of effective at controlling analgesic but does not pain relief every 6 hours pain as either dose of suggest potential for after the medication was codeine (120 mg or future studies to build off

given. 60 mg). of this (e.g., does not al. et Shin The nurse assessed pain The two tested doses of suggest the potential for intensity when the benzopyranoperidine testing increased doses medication was were no more effective of administered and every at controlling pain than benzopyranoperidines). hour after (for 6 hours). the placebo dose. Every hour, patients rated Compared with the their pain and answered placebo dose, both an 11-item doses of questionnaire. benzopyranoperidine appeared to enhance the participant’s pain perception. 4. Staquet, Determine the effects of a Two randomized, double- Data and NIB should not be used in 2b: Low- Sample sizes were small Gantt, & synthetic nitrogen blind trials. patients from practice because phase quality (30 patients in first trial; Machin, analog of The first trial compared hospitals in I studies have reported RCT 15 patients in second 1978. tetrahydrocannabinol 4 mg NIB, 50 mg Brussels, frequent side effects. trial). (NIB) on cancer pain. codeine, and a placebo. Belgium, and However, findings Patients were only There were 30 patients Chicago, Illinois suggest that nontoxic followed for 6 hours per included in this trial, and derivatives of medication (would have each patient received tetrahydrocannabinols been more effective if one of three medications may be effective in they followed patients over 3 consecutive days reducing cancer pain. using these medications (received a different In the first trial, NIB’s over a longer period). medication each day). effects on cancer pain Pain was measured The second trial compared was similar to codeine subjectively (provider 50 mg secobarbital, and more effective than perception) vs. 4 mg NIB, and a the placebo objectively (asking placebo. There were 15 In the second trial, NIB’s patients their pain level). patients included in this effect on cancer pain trial, and each patient was superior to the received one of the three placebo and medications within 3 secobarbital. consecutive days (after the 3 days each participant had received each medication over 1 day). Each day, the patient’s pain was monitored Pain Oncologic Adult in Cannabinoids and Cannabis subjectively every hour for 6 hours. Pain intensity differences (PIDs) were calculated by identifying how many hours (out of 6) a patient’s pain fell below his or her premedicated pain level. 5. Portenoy Evaluate a novel Randomized, double- Patients ‘‘There were no significant 2b: Low- The forced dose titration et al., cannabinoid blind, placebo- screened in differences in pain quality design potentially 2012. formulation, nabiximols, controlled, graded-dose 84 study response among RCT decreased ‘‘using a study design study. centers across different dose groups understanding of intended to obtain Participants were North America, that were randomized to analgesic efficacy and information about its randomly assigned to Europe, Latin placebo’’ (442). side effects. dose response for receive placebo or America, and No analgesic effect was Study did not titrate opioid analgesia and safety in a nabiximols at a low dose South Africa found in high-dose dosing based on pain population with (1-4 sprays/day), group, and high dose response from advanced cancer and medium dose (6-10 was not well tolerated nabiximols, preventing opioid-refractory pain," sprays/day), or high (high withdrawal rate evaluation of the opioid- (446). dose (11-16 sprays/ because of side effects) sparing effect of day). Low-dose nabiximols nabiximols. provided a 26% improvement in pain compared with baseline. Nabiximols have analgesic efficacy when given as an add-on therapy for patients with poor response to opioids. 6. Johnson, Determine the long-term ‘‘In total, 43 patients with 22 study ‘‘The efficacy end point of 2b: Cohort A total of 23 patients (59%) Lossignol, safety and tolerability of cancer-related pain sites, including change from baseline in study receiving THC/CBD Burnell- THC/CBD spray and experiencing 21 centers in mean Brief Pain spray and 1 patient

(Continued) 5 6

TABLE 1. Continued

Level of Citation Purpose Design/Method Setting Major Findings Evidence Limitations

Nugent, THC spray in relieving inadequate analgesia the U.K. and 1 Inventory-Short Form (25%) taking THC spray & Fallon, advanced cancer pain. despite chronic opioid in Belgium scores for ‘pain severity’ withdrew because of 2013. dosing, who had and ‘worst pain’ adverse effects participated in a domains showed a previous three-arm decrease (i.e., (THC/CBD spray, THC improvement) at each spray, or placebo), two- visit in the THC/CBD week parent spray patients. Similarly, randomized controlled the European trial, entered this open- Organization for label, multicenter, Research and Treatment follow-up study’’ (207). of Cancer Quality of Life ‘‘Patients self-titrated Questionnaire-C30 THC/CBD spray (n ¼ 39) scores showed a or THC spray (n ¼ 4) to decrease (i.e.,

symptom relief or improvement) from al. et Shin maximum dose and baseline in the domains were regularly reviewed of insomnia, pain, and for safety, tolerability, fatigue’’ (207-208). and evidence of clinical benefit’’ (207). 7. Bar-Sela Evaluate the advantages Prospective observational Rambam Health ‘‘Twenty-five (12%) 2b: Cohort Nature of the study leads et al., and side effects of using study included two Care Campus, patients stopped study to attrition—24% of the 2013. cannabis by cancer interviews based on Haifa, Israel treatment after less than study population died patients with medicinal questionnaires a week, mainly because before the second cannabis licenses. regarding symptoms of the side effects that follow-up interview, and and side effects, the first influenced their quality 10% did not use held on the day the of life or the absence of cannabis despite having license was issued and any clinical the license. There was the second 6-8 weeks improvement’’ (3). Of ‘‘lack of an appropriate later. ‘‘Cancer those with continuous control group for symptoms and cannabis cannabis use, ‘‘All comparison, since the side effects were cancer or anti-cancer overall improvement in documented on scales treatment-related perceived health quality from 0 to 4 following the symptoms, including might be attributed CTCAE. The distress nausea, vomiting, mood simply to time or other thermometer was used disorders, fatigue, factors unrelated to also’’ (1). ‘‘The data weight loss, anorexia, treatment’’ (7); also, collected included constipation, sexual ‘‘cannabis effects are information on the function, sleep only reported when self- cannabis use, such as disorders, itching, and report-based regular use or pain had significant methodologies are used interrupted’’ (2). improvement ( p < may imply that the ‘real’ .001)’’ (3). Seventy effect may be one of patients used pain psychological order, medication at the rather than specific beginning, of whom 2 effects on the body (1.7%) had dose physiology’’ (7). elevation and 31 (43%) dose reduction. 8. Lynch, Study nabiximols (oral Randomized, placebo- Participants ‘‘No statistically significant 2b: Low- 183 participants would Cesar- mucosal spray controlled crossover recruited difference [was found] quality have been required for Rittenberg, containing pilot study. through between the treatment RCT statistical significance. & cannabinoids) for the ‘‘Study drug was posters in and the placebo groups Hohmann, treatment of nabiximols, an oncology on the NRS-PI’’ (166). Pain Oncologic Adult in Cannabinoids and Cannabis 2014. chemotherapy-induced oromucosal whole clinics at ‘‘A responder analysis neuropathic pain. cannabis-based spray University demonstrated that there combining Teaching were five participants tetrahydrocannabinol Hospital who reported a two- with cannabidiol, minor (Capital point or greater cannabinoids and District reduction in pain that terpenoids, plus ethanol Health trended toward and propylene glycol Authority, statistical significance excipients, and Halifax, and the number needed peppermint flavoring’’ Nova Scotia, to treat was five’’ (166). (167). Canada) and Patients received drug for advertisements 4 weeks with pain in newspaper assessments on week 2 and 4 9. Fallon Assess the analgesic Both trials described were Study 1 was The primary efficacy 2b: Low- In both trials a significant et al., efficacy of adjunctive phase 3, double-blind, conducted at endpoints (percent quality number of participants 2017. Sativex (D9- multicenter, 101 centers in improvement, study 1, RCT withdrew from the study tetrahydrocannabinol randomized, placebo- Belgium, and mean change in (32% and 20.6% in (27 mg/mL): cannabidiol controlled trials. Study 1 Bulgaria, average daily pain NRS study 1 and 24.3% and (25 mg/mL) in advanced was a classic RCT Czech scores, study 2) were 14.6% in study 2 in the cancer patients with design. Study 2 had a Republic, not met in either study. therapy and placebo chronic pain two-part randomized Estonia, Post hoc analyses of the arms, respectively). unalleviated by withdrawal design. Germany, primary endpoints Moreover, the relatively optimized opioid Hungary, identified statistically high mortality rates therapy Latvia, favorable treatment reported in both studies Lithuania, effect for Sativex in U.S. (10% and 12.6%, and Poland, patients <65 years 22.3% and 9%) further Romania, (median treatment increased the number of the United difference: 8.8; 95% CI: lost patients. Kingdom, 0.00-17.95; p ¼ .040) Missing data are a well- and the that was not found in known factor that United States. patients <65 years from negatively affects study

(Continued) 7 8

TABLE 1. Continued

Level of Citation Purpose Design/Method Setting Major Findings Evidence Limitations

Study 2 the rest of the world outcomes. was conducted (median treatment The nature of the primary in 65 difference: 0.2; 95% CI: endpoints may have centers in 5.00 to 7.74; p ¼ .794). affected outcomes. Self- Australia, Treatment effect in favor reported NRS scores Bulgaria, of Sativex was found on can be associated with Germany, quality-of-life day-to-day variations in Hungary, questionnaires, despite mood, a phenomenon India, Israel, the fact that similar expected to have a Italy, Lithuania, effects were not found signiﬁcant impact in a Poland, on NRS score. The fragile population of Romania, safety proﬁle of Sativex patients with advanced Spain, was consistent with cancer. Taiwan, earlier studies, and no and the evidence of abuse or

United misuse was identiﬁed. al. et Shin Kingdom.

THC ¼ D9-tetrahydrocannabinol; RN ¼ registered nurse; CBD ¼ cannabidiol; CTCAE ¼ Common Terminology Criteria for Adverse Events; NRS ¼ Numeric Rating Scale; CI ¼ confidence interval. Cannabis and Cannabinoids in Adult Oncologic Pain 9 appropriate, the potential exclusion of studies as a Within the five databases (PubMed, MEDLINE, CI- result of differing terminology was reduced. NAHL, Embase, and Scopus), preference was given to The following search was conducted across the articles less than 5 years old, but because of limitations PubMed and MEDLINE databases: (marijuana OR "Can- in the quantity and quality of the literature published nabis"[Mesh] OR "Medical Marijuana"[Mesh]) AND within the last 5 years, the search was broadened to ("palliative care" OR "palliative medicine" OR "end of include older studies (since 1975), provided the study life" OR "pain") AND ("oncology" OR "cancer" OR evaluated the effect of cannabinoids or cannabis on "oncological pain") controlling cancer pain. The following search was conducted across the A total of 123 records were initially identified. Du- Web of Science, Embase, Scopus, and CINAHL data- plicates were removed using deduplicating tools built bases: (marijuana OR "Cannabis" OR "Medical Mari- into RefWorks, leading to 108 studies. Record juana") AND ("palliative care" OR "palliative screening was conducted based on title and abstract, medicine" OR "end of life" OR "pain") AND ("oncology" leading to the exclusion of 22 articles (based on exclu- OR "cancer" OR "oncological pain") sion criteria described previously), and 86 full-text arti- To be included, studies had to address the use of cles were assessed for eligibility. Full-text articles were cannabinoids or cannabis for pain management in excluded based on low level of evidence (n ¼ 23), oncology patients, either as standalone or adjuvant participant population (n ¼ 10), differing outcome therapy. In addition, the studies’ settings included criteria (n ¼ 33), systematic reviews (n ¼ 7), and not any country, not only the United States, because of being written in English (n ¼ 4). the more liberal legal policies surrounding cannabi- The researchers used a snowball method to noid usage internationally. Studies had to include pa- extract studies included in systematic reviews that tients who were 18 years old or older because of the were not included in the primary literature search legal and ethical implications of cannabis usage. (n ¼ 5) and then added these to the existing articles Studies had to have the full text available through uni- from the initial search that met inclusion criteria versity library means. Studies involving pediatric pa- (n ¼ 4). The final number of articles included in the ta- tients were excluded. Articles not written in English ble of evidence is nine articles (Table 1). The following were excluded. Studies that focused solely on patients study types were included: multiple multicenter, ran- with human immunodeficiency virus and multiple scle- domized, placebo-controlled trials, and two prospec- rosis were excluded. Articles that were case studies, tive observational survey studies. The studies were expert opinions, and qualitative studies were excluded graded by consensus of the researchers using the based on low level of evidence. Articles that could not Oxford Center for Evidence-Based Medicine levels of be accessed via the university libraries were excluded. evidence (2009) (Table 2). The methodology flowsheet of the integrative review is demonstrated in Figure 1.

TABLE 2. RESULTS Oxford Center Levels of Evidence for Therapy The studies reviewed analyzed the effect of cannabinoids and cannabis on oncology pain. To assess pain, Level Description five studies used the Numeric Rating Scale for Pain In- 1a SR (with homogeneity) of RCTs tensity (NRS-PI), three studies used a four-descriptor 1b Individual RCT (with narrow confidence interval) Verbal Rating Scale of Pain Intensity, and one used 1c All or none the Brief Pain Inventory (BPI) Short Form. The lack 2a Systematic review with homogeneity of cohort studies of standardized pain measurement tools decreased 2b Individual cohort study; low-quality RCT (e.g., the ability to compare results across studies. These <80% follow-up) three pain measurements scales have been found to 2c Outcome research; ecological studies be valid and to have sensitivity to changes in pain in 3a Systematic review with homogeneity of case- adult oncology patients (Jensen, 2003). The NRS-PI, control studies 3b Individual case-control studies however, has been found to be more sensitive than 4 Case series; poor quality cohort or case-control the Verbal Rating Scale (VRS) of Pain Intensity studies (Breivik, Bjornsson,€ & Skovlund, 2000). 5 Expert opinion omitting explicit critical appraisal Furthermore, a computerized simulation study (includes opinion based upon physiology, found that the NRS-PI had almost identical values in bench research, or first principles) the same patient at various times after surgery, SR ¼ systematic review; RCT ¼ randomized controlled trial. whereas the four-point VRS seemed to underestimate 10 Shin et al.

FIGURE 1. - Flowsheet of integrative review. the most intense pain compared with the NRS-PI studies) when analyzed using the Oxford Center for (Breivik et al., 2000). Moreover, Breivik et al. (2000) Evidence-Based Medicine therapy rating tool. THC found that after randomly sampling 10,000 times was administered through oral sprays and tablets. repeatedly from simultaneous observations of NRS Of these eight studies, five found THC to be more and VRS, the power to detect a difference in pain inten- effective than placebo (studies 1, 2, and 4-6), one sity was higher with the NRS compared with the VRS found THC to be more effective than placebo in Amer- data. Thus the NRS has higher sensitivity than the ican patients but ineffective in patients from other VRS. Researchers have found that the BPI Short Form countries (study 9), and two found THC to be no is valid and reliable for patients with medical and surgi- more effective than placebo (studies 3 and 8). Of cal cancer pain, with Cronbach a coefficients of the five studies that found THC to be more effective r ¼ 0.95 and r ¼ 0.97, respectively (Tan et al., 2004; than placebo, four noted that high-dose THC adminis- Tittle, McMillan, & Hagan, 2003). It is notable that tration resulted in a high-rate of negative side effects the studies analyzed by this paper used numerous amongpatients(studies1,2,5,and9).Ten- pain measurement tools, limiting the ability to milligram tablets of THC were generally well compare results across studies. tolerated, resulting in mild pain relief. The studies re- Of the nine studies reviewed, eight studies viewed suggest that the administration of low-dose (Table 1, studies 1-6, 8, and 9) reviewed the effect THC may provide a novel intervention for patients of the cannabinoid D9-tetrahydrocannabinol (THC, who have cancer pain refractory to opioids and con- the principal psychoactive component of cannabis) ventional pain management techniques. In addition, on cancer pain. The study designs had a level of evi- Bar-Sela et al. (2013) reviewed the use of medicinally denceof2b(sevenlow-qualityRCTsandtwocohort available whole plant cannabis (study 7). This study Cannabis and Cannabinoids in Adult Oncologic Pain 11 found that there was a significant decrease in pain potentially influenced patient reporting of drug effi- among those patients smoking cannabis; however, cacy and side effects. Furthermore, the primary the study has a lower level of evidence (IV) because research teams involved in the various studies often it was a prospective observational study. overlapped, potentially introducing a researcher bias. Studies included men and women suffering from a Moreover, because many of the studies used different broad spectrum of oncologic conditions, such as breast measures of pain (NRS, BPI, and VRS), it may be diffi- cancer, lymphoma, cervical cancer, and other cult to interpret findings across studies. However, in advanced cancers. Study participants were patients future studies, using the NRS and BPI pain measure from North America, South America, Europe, Asia, tools is recommended because of the greater validity Australia, and Africa. and reliability of these tools compared with the VRS. Finally, three studies only administered one dose of CONCLUSIONS AND LIMITATIONS the THC medication, which may not provide an appropriate understanding of how cannabinoids can affect Because of the limited number of studies available on long-term oncologic pain management. the efficacy of cannabis and cannabinoids in alleviating Although the studies reviewed had small sample adult cancer pain, it is challenging to make a definitive sizes, the patients included represented a wide demo- recommendation for practice. Although the current ev- graphic. Men and women with a broad spectrum of idence is sparse, there is sufficient evidence to support oncologic conditions were included. Study partici- further research into the use of low-dose THC in can- pants were patients from North America, South Amer- cer pain. The lack of evidence in this field of research ica, Europe, Asia, Australia, and Africa. This diversity in suggests a need to change policy surrounding cannabis study participants provided a broad demographic and cannabinoid research. Cannabis is a schedule I cohort of patients. drug, indicating there is no accepted medical use. Thus researchers must navigate a complex bureau- cracy to receive permission to study its effects. To pro- Implications for Nursing mote further research, nurses and other health care As the interest in cannabis and cannabinoid usage for professionals should lobby to remove cannabis from oncologic pain management grows, nurses have the the schedule I drug list, supporting the potential med- opportunity to advocate for further research and pol- ical uses. icy change. Nurses are able to directly support, There are several noteworthy limitations to the educate, and monitor patients’ oncology palliation pro- studies reviewed by this paper. Primarily, there is a cess, of which cannabis may play a role in the future. limited amount of high-quality evidence surrounding The pertinent implications for nursing practice include the use of cannabinoids and cannabis in oncology pa- the need to increase knowledge concerning the bene- tients, likely because of the legal issues surrounding fits and limitations of cannabis use, guiding patients’ cannabis. Many studies reviewed took place in foreign use of cannabis for palliative care, and empowering pa- countries, potentially limiting their application to the tients to make choices regarding cannabis use for can- United States. Only three of the nine studies analyzed cer treatment and palliation based on growing had a sample size larger than 50 patients, limiting the evidence. power of the results. Additionally, many studies had Cannabis and cannabinoids are still widely known high withdrawal rates, particularly in the study group. to be an illicit substance, and nurses may need to over- Several studies noted that individuals randomly as- come stigmas and fears surrounding its use. Nurses signed to cannabinoids were more likely to withdraw have the opportunity to empower patients through from the trial because of negative side effects, poten- the dissemination of the latest evidence. Through can- tially limiting the understanding of the negative side ef- did and evidence-based discussions about cannabis us- fects associated with cannabinoids. In addition, the age with patients, nurses can help to move the health classic side effects associated with cannabis and canna- care system beyond cannabis prohibition stigmas and binoids (such as feeling ‘‘high’’)often informed patients toward increased research on cannabis and cannabi- that they were receiving the study drug. This noids for use in oncology pain.

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