State of the evidence: Cannabinoids and cancer pain—A systematic review

Sydney Tateo, DNP, ARNP

Journal of the American Association of Nurse Practitioners


Abstract

Background and purpose: Cannabinoids are widely used to alleviate intractable symptoms such as pain, nausea, and muscle spasticity. The purpose of this review was to ascertain the current state of the science regarding use of cannabinoids for cancer pain.

Methods: Four electronic databases were searched for randomized control trials of cannabinoids and cancer pain. Studies included examined the analgesic effects of cannabinoids for cancer pain. Methodological quality was assessed using the Jadad scale.

Conclusions: Eight randomized control trials met the inclusion criteria for review. Most trials found analgesic effects from cannabinoids when compared to placebo, although not all associations reached statistical significance. The analgesic effects of cannabinoids were also limited by dose-dependent side effects. Side effects most commonly reported were changes in cognition, sedation, and dizziness.

Implications for practice: There is evidence that cannabinoids are effective adjuvants for cancer pain not completely relieved by opioid therapy, but there is a dearth of high-quality studies to support a stronger conclusion. Cannabinoids appear to be safe in low and medium doses. Methodological limitations of the trials limited the ability to make sound conclusions. Further research is warranted before efficacy, safety, and utility of cannabinoids for cancer pain can be determined.

Introduction

Cancer pain poses a significant problem in health care. It impacts patients, their families, and the healthcare providers involved in their care. It is estimated that over 14 million new cancer cases (excluding nonmelanoma skin cancers) are diagnosed each year worldwide, a number that is expected to increase 70% within the next 20 years (Ferlay et al., 2013). Approximately 32.6 million individuals are currently living with cancer worldwide, a statistic that will also grow drastically over the next few decades (Ferlay et al., 2013).

Pain may be experienced throughout all stages of cancer, with the highest prevalence in those with advanced disease. Two of three patients with cancerreport pain, with greater than a third of these patients grading their pain as moderate to severe (van den Beuken‐van Everdingen et al., 2007). Pain is arguably one of the greatest fears of cancer. Inadequate pain relief is associated with decreased quality of life, inability to perform daily activities, inability to cope, sleep disruption, depression, and anxiety (Liang et al., 2015; Sharma et al., 2012).

The management of cancer pain is a key component of oncology and palliative care (Portenoy, 2011). The World Health Organization's (WHO) pain relief ladder, introduced in 1986, is the cornerstone for guiding the treatment of cancer pain. The ladder identifies opioids as the principal drug for moderate to severe pain with additional nonopioids and adjuvants introduced as needed (World Health Organization, n.d.). Approved add‐on therapies may include nonsteroidal anti‐inflammatories (NSAIDs), corticosteroids, anticonvulsants, and antidepressants (Perez et al., 2015). Unfortunately, these drugs are not without side effects and despite following this regimen, a minority of patients, 10%–20%, will still experience significant pain (Benyamin et al., 2008; WHO, n.d.). Alternativestrategies must be taken to ameliorate pain in this population.

Cannabinoids for medical use today

Cannabinoids are gaining recognition in both the medical and legislative arenas. The growing body of medical research indicating therapeutic effects prompted legislators to legalize marijuana for specific medical uses in many states. Although the therapeutic effects of marijuana have gained popularity within the general population in recent years, marijuana's therapeutic benefits have been documented since 2,000 BC in ancient China.

Historically, cannabis was used to reduce inflammation, induce sleep, reduce pain, and treat rheumatism (Stack & Suddath, 2009). Marijuana was first introduced to the United States in the 1800s and was used for tetanus, rheumatism, analgesia, and convulsions (O'Shaughnessy, 1843). Marijuana remained an important drug through the 1900s, used as a sleep‐aid, analgesic (particularly for headaches), antispasmodic, and antidepressant. After the Second World War, a growing problem with drug use in the United States resulted in marijuana being grouped with narcotics as a drug subject to harsh criminal penalties for its use. It was banned in 1951 under a federal law known as the Boggs Act (Baron, 2015; McGeeney, 2013).

Today, marijuana and cannabinoids, such as delta‐9‐tetrahyrdocannabinol (THC) and cannabidiol (CBD), are classified by the U.S. Drug Enforcement Administration as Schedule I controlled substances. Neither marijuana nor cannabinoids can be prescribed under federal law (Kramer, 2015). The U.S. Food and Drug Administration (FDA, 2006) has not approved cannabis for medical use, citing a lack of safety and efficacy. However, marijuana is now legal in 23 states and the District of Columbia for medical use. Indications for medical marijuana include, but are not limited to, pain, nausea, spasticity, appetite stimulant, glaucoma, and posttraumatic stress disorder (Institute of Medicine, 1999).

Cannabis and the endocannabinoid system

Cannabis contains over 60 cannabinoids, the active chemical compounds, which are mainly found in the flowering tops and leaves of the cannabis plant. Cannabinoids act upon two types of cannabinoid receptors (CB receptors) located in membranes of nerve cells. These receptors play critical roles in appetite, cognition, memory, and pain perception. CB1 receptors are primarily found in the central and peripheral nervous system and suppress neuronal excitability (Rahn & Hohmann, 2009). CB2 receptors are predominantly located in immune tissue and are not responsible for psychoactive effects (Bowles, O'Bryant, Camidge, & Jimeno, 2012; Machado Rocha, Stefano, De Cassia Haiek, Rosa Oliveira, & Da Silveira, 2008). The CB receptors and endogenous cannabinoid receptor agonists, endocannabinoids, are known as the endocannabinoid system (Brenneisen, 2007).

THC, cannabinol, and CBD are the most active and widely used cannabinoids in healthcare research (Turcotte et al., 2010). THC is the main psychoactive ingredient, responsible for the mood‐altering effect of cannabis. Additionally, THC has analgesic, antiemetic, anti‐inflammatory, and antioxidant properties (Brenneisen, 2007). CBD is the other main cannabinoid investigated for medical use. While it does not produce the same euphoric, or “high” effects seen from THC, it does contain anxiolytic, antipsychotic, and anticonvulsive properties (Brenneisen, 2007). CBD has also shown to be effective in pain management, likely because of its anticonvulsant propensity (Kramer, 2015).

Although medical marijuana may not be legal in all states, patients will have questions regarding how this treatment option may or may not benefit them. The purpose of this review is to ascertain the current state of the science regarding the medical use of cannabinoids for cancer pain, including their therapeutic effects, side effects, and other implications of this treatment modality. This literature review sought to answer common questions that arise in the clinical setting using evidence found in the literature. Questions regarding efficacy, safety, route of administration, and dosing will be addressed.

Methods

A systematic review was conducted to appraise the literature on the medical application of marijuana for symptomatic relief of cancer pain. The search was conducted by a single researcher using PRISMA guidelines for evaluation of published articles. Studies were identified by searching the following electronic databases: BIOSIS (inception–present), CINAHL (inception–present), Cochrane Library (inception–present), and PubMed (inception–present). Terms searched included cancer painmarijuanacannabiscannabinoidsanalgesiacancerdronabinolnabiximols, and nabilone. The researcher also examined bibliographical references from all relevant studies for articles that may not have been found in the electronic database search. The PubMed “related articles” feature was also utilized. Studies in all languages were included in the search. Unpublished studies were not sought out. The researcher did an initial screen of all abstracts and omitted all irrelevant studies. Remaining full text articles were examined for inclusion in the review.

Inclusion criteria

To be included in this review, studies had to be randomized control trials (RCTs) performed on humans, examining the effects of cannabis or cannabinoids on cancer pain. Studies in which cannabinoids were examined for their effects on noncancer pain were excluded. Surveys, review articles, case reports/series, letters, and nonplacebo control trials were excluded. The search yielded 81 studies that were relevant to the topic. Eight studies met the inclusion criteria and were evaluated in this review. A summary of the search appears in Figure 1.

Data extraction

The researcher extracted the following data from the eight selected articles: study design, objectives, population, sample size, intervention (type, dose, and route of administration), outcome measures, outcomes, and adverse effects. All studies were also evaluated using the Jadad scale to assess the quality of the RCTs. This scale was designed for pain research and scores studies based on randomization, blinding, withdrawals, and dropouts (Jadad et al., 1996). It is a commonly used tool to assess methodological quality of RCTs when performing a meta‐analysis. A systematic review, appraising 21 scales used to assess methodological quality of RCTs, found that the Jadad scale has the highest validity of all the scales (Spearman r = .789) and has been tested for reliability in numerous settings (Olivo et al., 2008).

Results

Study characteristics

The eight RCTs, which enrolled a total of 683 patients, were analyzed in this systematic review (see Table 1). The number of participants per study ranged from 10 to 360 patients. All study participants were patients with cancer, suffering from moderate to severe pain related to their cancer. Six studies used a cross‐over design and two used a parallel‐group design. All examined the analgesic properties of cannabinoids for cancer pain; one study specifically examined neuropathic cancer pain.

 

Cancer pain poses a significant problem in health care. It impacts patients, their families, and the healthcare providers involved in their care. It is estimated that over 14 million new cancer cases (excluding nonmelanoma skin cancers) are diagnosed each year worldwide, a number that is expected to increase 70% within the next 20 years (Ferlay et al., 2013). Approximately 32.6 million individuals are currently living with cancer worldwide, a statistic that will also grow drastically over the next few decades (Ferlay et al., 2013).

Pain may be experienced throughout all stages of cancer, with the highest prevalence in those with advanced disease. Two of three patients with cancerreport pain, with greater than a third of these patients grading their pain as moderate to severe (van den Beuken‐van Everdingen et al., 2007). Pain is arguably one of the greatest fears of cancer. Inadequate pain relief is associated with decreased quality of life, inability to perform daily activities, inability to cope, sleep disruption, depression, and anxiety (Liang et al., 2015; Sharma et al., 2012).

The management of cancer pain is a key component of oncology and palliative care (Portenoy, 2011). The World Health Organization's (WHO) pain relief ladder, introduced in 1986, is the cornerstone for guiding the treatment of cancer pain. The ladder identifies opioids as the principal drug for moderate to severe pain with additional nonopioids and adjuvants introduced as needed (World Health Organization, n.d.). Approved add‐on therapies may include nonsteroidal anti‐inflammatories (NSAIDs), corticosteroids, anticonvulsants, and antidepressants (Perez et al., 2015). Unfortunately, these drugs are not without side effects and despite following this regimen, a minority of patients, 10%–20%, will still experience significant pain (Benyamin et al., 2008; WHO, n.d.). Alternativestrategies must be taken to ameliorate pain in this population.

Cannabinoids for medical use today

Cannabinoids are gaining recognition in both the medical and legislative arenas. The growing body of medical research indicating therapeutic effects prompted legislators to legalize marijuana for specific medical uses in many states. Although the therapeutic effects of marijuana have gained popularity within the general population in recent years, marijuana's therapeutic benefits have been documented since 2,000 BC in ancient China.

Historically, cannabis was used to reduce inflammation, induce sleep, reduce pain, and treat rheumatism (Stack & Suddath, 2009). Marijuana was first introduced to the United States in the 1800s and was used for tetanus, rheumatism, analgesia, and convulsions (O'Shaughnessy, 1843). Marijuana remained an important drug through the 1900s, used as a sleep‐aid, analgesic (particularly for headaches), antispasmodic, and antidepressant. After the Second World War, a growing problem with drug use in the United States resulted in marijuana being grouped with narcotics as a drug subject to harsh criminal penalties for its use. It was banned in 1951 under a federal law known as the Boggs Act (Baron, 2015; McGeeney, 2013).

Today, marijuana and cannabinoids, such as delta‐9‐tetrahyrdocannabinol (THC) and cannabidiol (CBD), are classified by the U.S. Drug Enforcement Administration as Schedule I controlled substances. Neither marijuana nor cannabinoids can be prescribed under federal law (Kramer, 2015). The U.S. Food and Drug Administration (FDA, 2006) has not approved cannabis for medical use, citing a lack of safety and efficacy. However, marijuana is now legal in 23 states and the District of Columbia for medical use. Indications for medical marijuana include, but are not limited to, pain, nausea, spasticity, appetite stimulant, glaucoma, and posttraumatic stress disorder (Institute of Medicine, 1999).

Cannabis and the endocannabinoid system

Cannabis contains over 60 cannabinoids, the active chemical compounds, which are mainly found in the flowering tops and leaves of the cannabis plant. Cannabinoids act upon two types of cannabinoid receptors (CB receptors) located in membranes of nerve cells. These receptors play critical roles in appetite, cognition, memory, and pain perception. CB1 receptors are primarily found in the central and peripheral nervous system and suppress neuronal excitability (Rahn & Hohmann, 2009). CB2 receptors are predominantly located in immune tissue and are not responsible for psychoactive effects (Bowles, O'Bryant, Camidge, & Jimeno, 2012; Machado Rocha, Stefano, De Cassia Haiek, Rosa Oliveira, & Da Silveira, 2008). The CB receptors and endogenous cannabinoid receptor agonists, endocannabinoids, are known as the endocannabinoid system (Brenneisen, 2007).

THC, cannabinol, and CBD are the most active and widely used cannabinoids in healthcare research (Turcotte et al., 2010). THC is the main psychoactive ingredient, responsible for the mood‐altering effect of cannabis. Additionally, THC has analgesic, antiemetic, anti‐inflammatory, and antioxidant properties (Brenneisen, 2007). CBD is the other main cannabinoid investigated for medical use. While it does not produce the same euphoric, or “high” effects seen from THC, it does contain anxiolytic, antipsychotic, and anticonvulsive properties (Brenneisen, 2007). CBD has also shown to be effective in pain management, likely because of its anticonvulsant propensity (Kramer, 2015).

Although medical marijuana may not be legal in all states, patients will have questions regarding how this treatment option may or may not benefit them. The purpose of this review is to ascertain the current state of the science regarding the medical use of cannabinoids for cancer pain, including their therapeutic effects, side effects, and other implications of this treatment modality. This literature review sought to answer common questions that arise in the clinical setting using evidence found in the literature. Questions regarding efficacy, safety, route of administration, and dosing will be addressed.

Methods

A systematic review was conducted to appraise the literature on the medical application of marijuana for symptomatic relief of cancer pain. The search was conducted by a single researcher using PRISMA guidelines for evaluation of published articles. Studies were identified by searching the following electronic databases: BIOSIS (inception–present), CINAHL (inception–present), Cochrane Library (inception–present), and PubMed (inception–present). Terms searched included cancer painmarijuanacannabiscannabinoidsanalgesiacancerdronabinolnabiximols, and nabilone. The researcher also examined bibliographical references from all relevant studies for articles that may not have been found in the electronic database search. The PubMed “related articles” feature was also utilized. Studies in all languages were included in the search. Unpublished studies were not sought out. The researcher did an initial screen of all abstracts and omitted all irrelevant studies. Remaining full text articles were examined for inclusion in the review.

Inclusion criteria

To be included in this review, studies had to be randomized control trials (RCTs) performed on humans, examining the effects of cannabis or cannabinoids on cancer pain. Studies in which cannabinoids were examined for their effects on noncancer pain were excluded. Surveys, review articles, case reports/series, letters, and nonplacebo control trials were excluded. The search yielded 81 studies that were relevant to the topic. Eight studies met the inclusion criteria and were evaluated in this review. A summary of the search appears in Figure 1.

Four different cannabinoids were tested in the eight studies: oral THC 5–32 mg, a standardized cannabis extract, nabiximols (THC:CBD) 2.7–43.2 mg/2.5–40 mg, oral synthetic nitrogen analogue of THC (NIB) 4 mg, oral benzopyranoperidine (BPP) 2–4 mg. No studies evaluated the analgesic effects of smoked, inhaled, or parenteral cannabinoids. Four studies also evaluated active treatment comparison drugs: oral codeine 50–120 mg and oral secobarbital 50 mg. All eight studies identified pain measures as their primary outcome. All studies also identified secondary outcomes, including sleep quality, quality of life, side effects, and cognitive ability, although not all studies contributed data for each secondary outcome listed.

THC versus placebo

Noyes, Brunk, Baram, and Canter (1975a) examined the analgesic effects of oral THC versus an identical placebo for cancer pain. The study, involving 10 participants with various malignancies, examined the analgesic effects of a placebo, 5, 10, 15, and 20 mg oral THC. The intervention was administered once daily, and both pain reduction and pain relief scores were measured. All doses of THC were found to have an analgesic effect when compared to the placebo. The results revealed a significant trend toward increasing pain relief with increasing THC doses (p‐value < .001). Significantly higher pain relief was documented when high doses of THC were administered (15 and 20 mg; p‐value < .025; Noyes et al., 1975a).

Secondary outcomes

The researchers of this study also examined side effects and physiologic response as secondary outcomes. Side effects most commonly reported included drowsiness, mental cloudiness, slurred speech, blurred vision, and dizziness. Sedation was most common and more severe in patients receiving high doses of THC. Heart rate and blood pressure decreased in those who received 15 and 20 mg doses. While greater analgesia was achieved with 20 mg dose, marked side effects were noted, resulting in little clinical value of THC at this dose (Noyes et al., 1975a).

THC versus codeine versus placebo

Noyes, Brunk, Avery, and Canter (1975b) examined the analgesic effects of oral THC, compared to oral codeine and a placebo. The study, involving 36 participants with various malignancies, examined the analgesic effects of a placebo, THC 10 mg, THC 20 mg, codeine 60 mg, and codeine 120 mg. The intervention was administered orally, once daily. Both pain reduction and pain relief scores were measured. All doses of THC and codeine were found to have an analgesic effect when compared to the placebo. THC 10 mg and codeine 60 mg provided comparable pain reduction and pain relief scores. Similarly, THC 20 mg and codeine 120 mg also produced parallel results. Both THC 20 mg and codeine 120 mg produced significant analgesia when compared to the placebo (p‐value < .05; Noyes et al., 1975b).

Secondary outcomes

The researchers of this study also examined side effects and physiologic response as secondary outcomes. Patients receiving high doses of THC (20 mg) reported severe sedation. Participants voiced dislike over the marked cognitive side effects experienced with high doses of THC. Five patients discontinued the study because of adverse reactions to THC. These reactions consisted of extreme anxiety and sense of loss of control. These adverse effects limit the therapeutic use of THC 20 mg (Noyes et al., 1975b).

BPP versus codeine versus placebo

Jochimsen, Lawton, VerSteeg, and Noyes (1978) examined the analgesic effects of oral BPP, a congener of THC, compared to oral codeine and a placebo. The study, involving 37 participants with various malignancies, examined the analgesic effects of a placebo, BPP 2 mg, BPP 4 mg, codeine 60 mg, and codeine 120 mg. The intervention was administered orally, once daily. Both pain relief and pain intensity were measured after administration of the intervention. No significant difference in pain scores was recorded between placebo and any other active treatment. Codeine 120 mg ranked highest of all treatments for pain relief, although only 19 of 35 participants recognized it as effective. When compared to the placebo, patients who were administered BPP had poorer response rates. Patients experienced poor pain relief and ranked pain intensity as higher, indicating that pain perception was in fact augmented by both doses of BPP (Jochimsen et al., 1978).

Secondary outcomes

Side effects and physiological responses were also examined as secondary outcomes. Both patient report and physical examination failed to reveal any significant side effects, physiologic changes, or adverse reactions from the intervention (Jochimsen et al., 1978).

NIB versus codeine versus placebo

Staquet, Gantt, and Machin (1978) examined the analgesic effects of a synthetic NIB, compared to oral codeine and a placebo. NIB, an analog of THC, had previously been examined in animal research indicating analgesic activity. The study, involving 30 participants with various malignancies, examined the analgesic effects of a placebo, NIB 4 mg, and codeine 50 mg. The intervention was administered orally, once daily. Pain intensity was measured after administration of the intervention. Significant pain intensity differences were found between both the placebo and codeine, and placebo and NIB (p‐value < .05), indicating that both treatment drugs were superior to the placebo. NIB was about equipotent to codeine; no significant difference between the two existed (Staquet et al., 1978).

Secondary outcomes

Side effects and physiological responses were also examined as secondary outcomes. Both patient report and physical examination failed to reveal any significant side effects, physiologic changes, or adverse reactions from the intervention. Drowsiness was the only side effect reported for all treatments, although it was most common after the administration of codeine (Staquet et al., 1978).

NIB versus secobarbital versus placebo

Staquet et al. (1978) examined the analgesic effects of a synthetic NIB, compared to oral secobarbital and a placebo. The study, involving 15 participants with various malignancies, examined the analgesic effects of a placebo, NIB 4 mg, and secobarbital 50 mg. Pain intensity was measured after administration of the intervention. NIB was the only treatment to achieve significant analgesia compared to the placebo (p‐value < .01). There was no reported difference between the placebo and secobarbital (Staquet et al., 1978).

Secondary outcomes

Side effects and physiological responses were also examined as secondary outcomes. Both patient report and physical examination failed to reveal any significant side effects, physiologic changes, or adverse reactions from the intervention. Drowsiness was the only side effect reported for all treatments, although it was more common after administration of NIB compared to secobarbital (Staquet et al., 1978).

Nabiximols versus placebo

Two studies examined the analgesic effects of nabiximols, or THC:CBD, compared to a placebo. Nabiximols is a cannabis‐based oromucosal spray containing a fixed ratio of the plant extracts THC and CBD. Rather than synthetic, Portenoy et al. (2012), involving 360 participants with various malignancies, examined the analgesic effects and safety of a placebo versus three dose ranges of nabiximols. Patients randomized to the low‐dose treatment group received 1–4 sprays/day; the medium dose group received 6–10 sprays/day; and those in the high dose group received 11–16 sprays/day. The interventions were delivered as an oromucosal spray; each spray of the active treatment contained a fixed dose of 2.7 mg of THC and 2.5 mg of CBD. The primary outcome measured was pain response rate. Patients responded to a series of questions in which they rated from 0 to 10 their average pain, worst pain, need for breakthrough pain relief, and use of scheduled, fixed‐dose opioids. A 30% or more reduction in pain indicated a positive response rate. The responder rate analysis indicated no statistically significant difference between nabiximols and the placebo (p‐value = .59). Researchers conducting further analyses on average daily pain from baseline to conclusion of the study found that patients receiving nabiximols reported significantly greater analgesia compared to those in the placebo group (p‐value = .035), specifically in the low‐dose group (p‐value = .008) and medium dose group (p‐value = .039; Portenoy et al., 2012).

The second study, Lynch, Cesar‐Rittenberg, and Hohmann (2014), involving 18 participants with various malignancies, examined the analgesic effects of a placebo versus nabiximols on neuropathic pain secondary to chemotherapy. The interventions were delivered as an oromucosal spray; each spray of the active treatment contained a fixed dose of 2.7 mg of THC and 2.5 mg of CBD. Patients self‐titrated the dose of the treatment until they reached a dose that relieved the pain, but not to exceed 12 sprays/day. The mean dose used by patients in the active treatment group was 8 sprays/day, and 11 sprays/day for those in the placebo group. The primary outcome measure was a change in pain intensity ratings from baseline. While 5 of the 18 patients (28%) reported significant reduction in pain, analyses indicated no statistically significant difference in pain ratings between the placebo group and those receiving nabiximols (Lynch et al., 2014).

Secondary outcomes

Both studies also examined secondary outcomes. Portenoy et al. (2012), comprising 360 participants, examined sleep disruption, overall quality of life, impression of global change, and side effects. Overall, sleep disruption was improved (p‐value = .012), with patients in the low‐dose group experiencing a significant improvement in sleep (p‐value = .003). While the majority of secondary subscales revealed no significant difference between active and placebo treatment groups, a significant proportion of participants in the active group reported nausea and vomiting (p‐value = .019). Other common, but not significant side effects documented include dizziness and disorientation. Adverse events were dose‐related, with only participants in the high‐dose group comparing unfavorably with the placebo (Portenoy et al., 2012).

Lynch et al. (2014), comprising 18 participants, examined quality of life, sensory function, and adverse events attributed to the intervention. Analyses of subscales used to measure quality of life and sensory function demonstrated no significant effect compared to the placebo. The participants reported no significant side effects. The most common side effects were fatigue, dizziness, dry mouth, and nausea (Lynch et al., 2014).

Nabiximols versus THC versus placebo

Johnson et al. (2010) examined the analgesic effects of nabiximols, or THC:CBD, compared to oral THC and a placebo. The study involved 177 participants with various malignancies. The interventions were delivered as an oromucosal spray; each spray of the active nabiximols treatment contained a fixed dose of 2.7 mg of THC and 2.5 mg of CBD and each spray of the THC active treatment contained a fixed dose of 2.7 mg of THC alone. Patients self‐titrated the dose of the treatment (approximately 8–12 sprays/day) until they reached a dose that relieved their pain, or undesired side effects were experienced. The mean number of sprays used per day for the nabiximols group was 8.75, THC group 8.34, and placebo group 9.61. Researchers identified two coprimary outcomes; change in pain scores from baseline and use of breakthrough analgesia. Analyses indicated a significant pain reduction in those treated with nabiximols (p‐value = .014), but no significant reduction in those treated with THC alone (p‐value = .245). Twice as many participants treated with nabiximols experienced a reduction of pain greater than 30% from baseline compared to the placebo group. No significant differences were noted in the use of breakthrough analgesia in any treatment group (Johnson et al., 2010).

Secondary outcomes

The study also examined several secondary outcomes: use of opioid background medication, memory, sleep quality, quality of life, side effects, and global functioning. Statistically significant side effects recorded were reduction in cognitive function in both active treatment groups and nausea/vomiting in the nabiximols treatment group. Memory significantly improved in the placebo group, whereas it declined in both active treatment groups. Appetite was also significantly reduced in those treated with nabiximols and THC. However, despite the documented side effects, treatments were well tolerated by patients (Johnson et al., 2010).

Discussion

Methodological quality

The eight studies included in this review are of low or moderate quality according to measures assessed by the Jadad scale. The Jadad scale is a tool used to measure methodological quality of controlled trials. Studies are scored out of five points based on three components: randomization, blinding, and accounting for attrition/dropouts. An additional point is awarded in each of the first two categories if the methods used for randomization and blinding are appropriate. Scores on these factors are then summed, and the study is classified as high quality, moderate, or low quality (Jadad et al., 1996). Jadad scores for each study are shown in Table 1. Using the Jadad scale, Noyes et al. (1975a 1975b) and Jochimsen et al. (1978) scored three of five, indicating low‐quality study design. These studies failed to discuss withdrawals and dropouts. Without discussion of study withdrawals and dropouts, it is impossible to validate study results (Dettori, 2011). Additionally, Lynch et al. (2014) scored four of five on the Jadad scale, also omitting loss to follow‐up, categorizing it as a low‐quality study. The remaining four RCTs scored four of five, accounting for the presence of randomization, blinding, and discussion of loss to follow‐up, but inadequately describing either randomization or blinding methods.

All studies used a placebo group. All studies also used a randomized, double‐blind design. Adequate blinding was achieved by seven of the eight studies by using placebo treatments that were identical in appearance to the intervention treatment. Portenoy et al. (2012) failed to mention how blinding was achieved so it is unknown if the method was adequate.

Summary of Results

Eight RCTs were included in this systematic review. The studies examined a range of cannabinoids: oral THC, nabiximols, oral synthetic NIB, and oral BPP. The majority of these studies found analgesic effects from cannabinoids when compared to placebo, although not all associations reached statistical significance.

There is low‐quality evidence suggesting that cannabinoids are effective analgesics for cancer pain. The strongest evidence supporting the analgesic effects of cannabinoids exists for nabiximols. Three of the eight studies examined nabiximols, all reporting a decrease in pain measures, although Lynch et al. (2014) did not reach significance. Few significant side effects or adverse reactions were reported in these studies, the most common being cognitive changes and dizziness. Portenoy et al. (2012) also documented improvement in sleep in those receiving low and medium doses of nabiximols.

There is low‐quality evidence indicating THC is not a useful analgesic for cancer pain. Three of the eight studies examined THC. Johnson et al. (2010) found no analgesic effects of THC. While Noyes et al. (1975a 1975b) report pain reduction in those who received all doses of THC, statistically significant results were only achieved in high‐dose groups. Significant cognitive impairment and dizziness were recorded for these groups, limiting the utility of THC at these doses.

There is low‐quality evidence indicating NIB and BPP are not useful analgesics for cancer pain. While Staquet et al. (1978) reported analgesic effects from NIB, the researchers conclude that it is not clinically useful because of the frequency and severity of side effects. While the researchers did not record frequent side effects, they state that a phase I study determined NIB was not suitable for clinical use because of side effects (Staquet et al., 1978). Jochimsen et al. (1978) reported no analgesic effects of BPP. In fact, pain measures worsened in those administered BPP.

Completeness and applicability of the evidence

Large gaps exist in the data in regards to efficacy, safety, dosing, route of administration, and long‐term effects of cannabinoids for cancer pain. It comes as a surprise that so little robust research has been conducted on this topic over the past several decades. It is possible that significant publishing bias exists against this topic, and that additional studies have been conducted that were either not submitted or selected for publication. It should also be noted that this review contains publishing bias, as unpublished, or gray literature is not represented within this review.

It is challenging to study the effects of medical marijuana, not only because of legal restrictions and subsequent lack of support for funded research, but because as an herbal product, there can be significant variability in the levels of pharmacologically active components of the plant. Where legalization has occurred, it has not been based on strong scientific evidence of specific benefits. In addition, the studies included in the review examined various forms of cannabinoids, making it difficult to draw conclusions regarding any one particular type of cannabinoid's efficacy and utility (National Center for Complementary and Integrative Health, 2016).

While the original goal of this review was to serve as a resource for clinicians, it in fact may be a more useful resource for researchers. This review should be used by researchers to identify areas in which more research is warranted. Future trials should aim to produce high‐quality evidence by ensuring appropriate methods are used for randomization, allocation concealment, blinding, handling of withdrawals and dropouts, and avoiding selective outcome reporting (Whiting et al., 2015). Further research is needed for all topics regarding cannabinoids: efficacy, safety, dosing, and route of administration. There is also a great gap in the evidence regarding long‐term effects of cannabinoid use in both healthy and ill populations. Because the strongest evidence exists for nabiximols, researchers should focus future research on this cannabinoid. Only once there is a greater body of knowledge regarding cannabinoids and their utility in pain management as well as secondary outcomes (i.e., sleep and quality of life) can we begin to objectively determine the risk:benefit profile of these substances.

Several other systematic reviews regarding cannabinoids for human pain have been published. While many of these reviews are limited to noncancer pain (i.e., neuropathic pain, arthritic pain, pain related to muscle spasticity), the overarching consensus is that of uncertainty. While cannabinoids show promising analgesic properties for chronic and neuropathic pain, these effects may be offset by side effects such as cognitive impairment (Lynch & Campbell, 2011; Martín‐Sánchez, Furukawa, Taylor, & Martin, 2009). These reviews acknowledge the potential cannabinoids possess, but reviewers universally agree that more high‐quality research must be conducted in order to determine the scope in which cannabinoids are suitable for use as well as short‐ and long‐term safety profile.

While this review may not provide specific recommendations regarding administration, dosing, monitoring, etc., it does provide clinicians with an accurate picture of the current state of the evidence. Perhaps the strongest take‐home message is that while the current evidence shows encouraging data for the use of cannabinoids, far too little rigorous research exists to be able to safely recommend cannabinoids as analgesics. Until more evidence exists regarding cannabinoids for cancer pain, clinicians should caution against the use of cannabinoids as analgesics.

Conclusion

The eight studies included in this review were of low or moderate quality. There is evidence that cannabinoids are effective adjuvants for cancer pain not completely relieved by opioid therapy, but there is a dearth of high‐quality studies to support a stronger conclusion. Cannabinoids appear to be safe in low and medium doses, with no serious adverse effects noted in these dose ranges. Methodological limitations of the trials limited the ability to make sound conclusions. This review showed encouraging evidence that cannabinoids are effective analgesics, meriting additional investigation. Further research is warranted before efficacy, safety, and utility of cannabinoids for cancer pain can be determined.


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