Pain and Opioids in Cancer Care: Benefits, Risks, and Alternatives
Publication: American Society of Clinical Oncology Educational Book
Pain remains a disturbingly common consequence of cancer and its treatment. In a large study of more than 5,000 adults with cancer, 56% suffered moderate to severe pain at least monthly.1 A large systematic review of 52 studies confirmed this high prevalence, with 53% of people at all stages of cancer experiencing pain.2 Although there is evidence that the management of cancer pain has improved, under-treatment remains common and new challenges are threatening the fragile progress that has previously been made.3 These challenges are numerous and include educational deficits, time restraints, and limited access to all types of care.4 Comprehensive cancer pain management includes a thorough assessment along with the use of pharmacologic, nonpharmacologic, integrative, and interventional therapies.5 Reimbursement for many of these therapies is limited, particularly for nonpharmacologic techniques such as mental health counseling, physical or occupational therapy, massage, and integrative medicine. As a result, access to cancer pain management is often restricted to pharmacologic therapies.
Opioids are the mainstay of this pharmacologic management and are essential for those with pain from advanced disease. However, our evolving understanding of the risks of long-term adverse effects, including the potential for misuse or abuse, raises concerns about the long-term use of opioids for cancer survivors.6 These challenges surrounding the use of opioids, and the need for safe and effective alternative analgesics, are leading to intense interest in the potential benefits of cannabis for cancer-related pain.
Opioids in Advanced Cancer: Access, Efficacy, and Outcomes
Access
Cancer that is locally progressive or has metastasized is frequently painful. A systematic review by van den Beuken-van Everdingen showed that pain prevalence rises with disease progression and affects about 64% of patients with advanced cancer.2 About 45% of all patients with advanced cancer experience pain of moderate to severe intensity (at least 5 on a 0–10 pain rating scale).1,2
Morphine and other strong opioids are key to managing pain in advanced cancer. Since 1986, the focus of cancer pain treatment has been the use of strong opioids based on the World Health Organization’s (WHO’s) “analgesic ladder.”7 Globally, 8.2 million people die of advanced cancer each year, and the WHO estimates that around 6 million of these patients have inadequate or no access to strong opioids largely because there has been no increase in availability of opioids for decades in the world’s poorest but most populated countries.8,9 This is largely because of government regulations that restrict supply and access.10 Even in developed countries in which there is good access to opioids, at least 32% of patients with cancer are undertreated for their pain.3 There is understandable concern about abuse of prescription opioids in contexts other than advanced disease, and there is increased tightening of prescribing regulations for opioids in the United States in particular.11 This restrictive attitude toward opioids should not be allowed to exacerbate the existing undertreatment of pain in advanced cancer.12
Retrospective cohort analyses estimate that only 43%–48% of U.K. patients with cancer receive a strong opioid before their death,13,14 though this might be as high as 60% in Norway.15 Ziegler et al14 demonstrated that median time between initiation of strong opioids and death for 6,080 patients was 9 weeks, with increasing age associated with significantly later initiation of treatment, consistent with other studies.13,15 Patients who died in the hospital were less likely to be prescribed a strong opioid while at home, compared with those who died in hospice, and were more likely to commence strong opioids late. These variations were not explained by cancer type, duration of disease, or socioeconomic deprivation. This suggests that poor pain control at home may result in admission to and subsequent death in the hospital. Therefore, earlier pain assessment might lead to improved access to opioids and improved outcomes for patients.
Even in developed countries, patients with cancer appear to access strong opioids relatively late in their disease. One methodological issue with these epidemiologic data are that they cannot be matched with individual patient-reported pain data. This means that it remains uncertain whether this pattern of opioid access closely matches the patients’ onset of pain before death or highlights undertreatment. The latter seems more likely based on known epidemiology of duration of cancer pain in large cohorts.1
Efficacy
How effective are strong opioids for patients with cancer pain? Initial observational studies that evaluated the WHO ladder suggested that this approach could control pain in around 73% of patients with cancer.16,17 In absolute terms, one randomized trial that compared morphine with oxycodone in patients with cancer pain showed that both strong opioids provided good pain control in 75% of patients.18 Both strong opioids produced approximately a 3-point mean reduction on a 0–10 pain rating scale at a group level, although these data were not compared with response to placebo. There were no differences in adverse effects.
A meta-analysis of clinical trials of strong opioids has provided more detailed and comparative data. The National Institute for Health and Clinical Excellence (NICE) in the United Kingdom published a detailed meta-analysis confirming that there were no significant differences in efficacy between morphine, oxycodone, transdermal fentanyl, and transdermal buprenorphine.19 Specifically, there were no differences in efficacy or adverse effects between morphine and oxycodone—probably the most frequently prescribed strong opioids for cancer pain globally.20 Overall, there were no differences in burden of adverse effects across all strong opioids, though transdermal opioids were significantly less likely to cause constipation than oral opioids (odds ratio 0.43; p < .002).
Another recently published randomized trial directly compared these same four strong opioids (morphine, oxycodone, transdermal fentanyl, and transdermal buprenorphine). Corli et al21 showed no differences in efficacy between all opioids (all of which produced approximately a 3-point mean reduction on a 0-10 pain rating scale at a group level) and, interestingly, showed no differences in prevalence of constipation. The only significant differences occurred between morphine and fentanyl in the incidence of hallucinations (13.2% vs. 2.4%; p = .001) and severe confusion (15.5% vs. 6.3%; p = .018) that favored transdermal fentanyl.
In summary, strong opioids are very effective interventions for cancer pain resulting in a 75% response rate and reducing average pain intensity from 6 to 3 on a 0–10 pain scale.20,21 When compared with the early evaluations of the WHO analgesic ladder, these more recent data imply that the effectiveness of the WHO approach is based entirely on strong opioids, with no substantial contribution from other approaches. These studies underpin international guidance on strong opioids for cancer pain that advises first-line treatment with either morphine, oxycodone, transdermal fentanyl, or transdermal buprenorphine based on efficacy.5,22 In the United Kingdom, NICE guidance recommends morphine as a first-line opioid because of its substantially cheaper cost.19
Outcomes
What is a meaningful outcome for a patient with cancer pain? Understandably, patients express that they want to be pain free, although, in general, they do not actually expect their pain to be relieved completely.23 Bender et al24 identified that patients are keen to understand the cause of their cancer pain, what to expect, options for pain control (including addressing concerns about strong opioids), and how to cope with cancer pain including talking with others and finding help. A number of qualitative studies have revealed that patients seem to determine whether their pain is controlled by whether they can perform activities or tasks and maintain relationships with family or friends.24,25
To perform these activities, patients frequently try to reduce interference from both pain and the cognitive effects of analgesia to maintain as much function as possible.26 This commonly leads to trade-offs between pain and analgesia, impacting medication adherence. The concept of trading off has not been well described in medical literature, but it is clearly seen as important by patients in reaching outcomes that are meaningful for them. For this reason, clinicians should seek to understand patient preferences for cancer pain management when initiating and managing strong opioids.
Key priorities for clinicians regarding pain management strategies for patients with advanced cancer should be to help them achieve a balance between pain and adverse effects of analgesia to optimize physical function and to provide support for self-management.27,28 Overly simplifying these important outcomes to a numerical rating of pain intensity is likely to be poorly sensitive (patients may be content with the balance of their pain management yet report higher pain scores) or poorly specific (patients may judge their pain control unsatisfactory despite lower pain scores because they struggle with opioid adverse effects, which severely limits their function). A focus on determining interference from pain or analgesia in daily activities and understanding the degree of self-efficacy (ability to cope) are more important measures of successful pain management.
Opioids in Cancer Survivors: Benefits, Risks, and Challenges
Currently, there are approximately 15.5 million cancer survivors in the United States, and this number is expected to grow to 26.1 million by 2040.29 Of these individuals, more than two-thirds have lived 5 years or more after diagnosis, and 44% have survived 10 years or more.29 Much of these impressive figures in survivorship are because of extraordinary advances in the development of more effective cancer therapies. Unfortunately, many of these highly effective treatments also lead to persistent pain syndromes. As a result, studies suggest the prevalence of pain in cancer survivors may be 40% or higher.2,30,31
Benefits and Risks
Although opioids have a clear and primary role in the care of pain associated with advanced disease, their role in relieving pain in cancer survivors is less apparent. The recent ASCO Clinical Practice Guideline Management of Chronic Pain in Survivors of Adult Cancer outlines the results of a systematic review of studies investigating chronic pain management in cancer survivors.6 One systematic review of randomized controlled trials of opioids for relief of cancer pain found few high-quality, long-term trials.32 In a large study of more than 500 subjects randomly assigned to receive one of four opioids for 28 days, the worst and average pain intensity decreased over 4 weeks with no significant differences between drugs.21 Changes in therapy, including dose escalation, switches to other opioids, and the addition of adjuvant analgesics, were common, and close to 15% of patients were nonresponders.21 Although clinical experience suggests that select patients may obtain safe and effective pain control with opioids, there are no studies that guide clinicians as they consider a trial of opioids in cancer survivors.
Aligned with unclear long-term efficacy is an increasing awareness of the adverse effects associated with prolonged use of opioids (Sidebar). Mental clouding, effects on libido and fertility, hyperalgesia, and sleep disorders can all affect employment, relationships, and overall quality of life.33-35 Provocative and troubling early data from laboratory models suggest that opioids may affect immune function36,37 and tumor progression,38,39 yet it is too early to determine if these findings are clinically meaningful. Of particular concern in the face of the current opioid abuse epidemic is that cancer survivors treated with opioids may also develop opioid or other substance abuse disorders as has been documented in people with chronic noncancer pain.11,40,41
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Constipation
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Mental clouding
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Upper gastrointestinal symptoms (pyrosis, nausea, bloating)
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Endocrinopathy (hypogonadism/hyperprolactinemia)
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Fatigue
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Infertility
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Osteoporosis/osteopenia
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Reduced libido
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Reduced frequency/duration or absence of menses
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Neurotoxicity
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Myoclonus
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Other changes in mental status (including mood effects, memory problems, increased risk of falls in elderly patients)
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Risk of opioid-induced hyperalgesia (incidence and phenomenology uncertain, but escalating pain in tandem with dose-escalation raises concern)
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Sleep-disordered breathing
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Increased risk of concurrent benzodiazepine in patients predisposed to sleep apnea
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New-onset sleep apnea
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Worsening of sleep apnea syndromes
Risk Mitigation
Methods to mitigate the risk of harm include careful assessment and awareness of adherence monitoring. Screening tools are available to determine risk of misuse, although none have been validated in an oncology population to date. Key factors that have been found to be associated with opioid misuse/abuse in those with a noncancer diagnosis include male sex, age younger than 65, opioid misuse history, depression, family history of substance use disorders, current smoking, past or current incarceration, and post-traumatic stress disorder.42-45
Adherence monitoring may include use of a controlled substance agreement, review of data from prescription drug monitoring programs, periodic drug testing, pill counts, and education.46-51 After review of assessment data and information obtained from urine drug screening and a prescription drug monitoring program, a decision is made to prescribe based on risk stratification. If risk is low and the pain warrants use of an opioid, the oncologist may decide to prescribe. If the risk of abuse is moderate or high, the oncologist must decide if the severity of the pain is seriously affecting the patient’s physical or mental well-being and if there are reasonable alternatives. If the effect of pain is severe and there are no other reasonable alternatives, and the risk of abuse and/or diversion is manageable, a trial of opioids may be considered. Regardless of level of risk, nonopioid and nonpharmacologic therapies should always be optimized.
If opioids are prescribed, adherence monitoring should continue, with the frequency dictated by the level of risk (Table 1).6 If opioids are ineffective or serious adverse effects occur, careful reconsideration of therapy must occur.
Given the severity of the opioid misuse/abuse epidemic, oncology clinicians must be attentive to the potential for diversion, and those with cancer may be targeted as potential sources of prescription drugs. Education about safe storage and disposal has been shown to increase awareness and improve safe practice by patients.52
Cannabinoids in Cancer Pain Management
Over the past 20 years, the public and medical community’s attitude toward cannabinoids has been shifting. Although it remains illegal federally, over half of the U.S. states have legalized the medicinal use, with a handful legalizing recreational use. With this changing landscape comes many challenging questions from oncology providers and patients:
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What role do cannabinoids play in alleviating pain?
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Should physicians recommend cannabinoids for the treatment of pain, particularly pain related to cancer?
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What are the risks and side effects?
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How do patients obtain and use a cannabinoid drug?
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How should physicians who choose to recommend cannabinoids select appropriate patients and monitor them?
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What are the legal and regulatory issues that providers and researchers face in dealing with cannabinoids?
Cannabis Content
The cannabis plant contains over 400 chemical compounds, of which at least 80 are cannabinoids.53 Delta-9-tetrahydrocannabinol (Δ9-THC) is the most well-known and the primary psychoactive compound in cannabis.54-56 It mimics the action of anandamide, an endogenous cannabinoid in humans, having approximately equal affinity for the CB1 and CB2 receptors.
Cannabidiol (CBD) is the second most abundant compound in cannabis after THC.55 It is thought to have wider medical applications than THC, which has fueled the demand for medical marijuana and pharmaceuticals with higher CBD concentrations compared with recreational marijuana.57 CBD is generally considered to have no psychoactive effects, but clinically it has been reported to reduce seizures, improve muscle spasm, and reduce inflammation.54,56 It has a very low affinity for the CB1 and CB2 receptors and may act as an inverse agonist/antagonist.54,55 These interactions with the CB receptors may attenuate some of the psychotropic effects of THC.54
In addition to whole-leaf cannabis plants, there is another class of phytocannabinoids collectively referred to as cannabis-based medicine extracts. These are derived by extracting compounds directly from cannabis plants. There are two subtypes of cannabis-based medicine extracts: (1) those produced by pharmaceutical companies under well-regulated, controlled conditions and undergoing rigorous clinical trials and (2) those produced and sold in medical marijuana dispensaries without any regulatory oversight or clinical trials.
Pharmacology of Cannabinoids
The precise pharmacology of most cannabinoids remains unknown. However, researchers have elicited major mechanisms underlying the active compounds in cannabis including THC, CBD, and cannabinol. Complicating this is the highly variable absorption because of the plethora of delivery forms and routes. These include inhalation and ingestion as well as absorption via oral, sublingual, topical, or rectal application.58 For centuries, the primary means of delivering cannabinoids has been via the inhaled smoke of cannabis or hashish. The variable concentration of THC and other cannabinoids in cannabis, lack of controlled production and testing in most medical marijuana products, and the diversity of delivery routes makes prediction of pharmacologic effects difficult.56
In general, the inhalation of cannabis results in a fast predictable plasma concentration of cannabinoids that is short lived allowing for fine titration to affect. Ingestion results in a delayed, variable peak plasma concentration that is more prolonged. Transmucosal delivery results in peak plasma levels similar to ingestion but more rapid and of shorter duration. These different delivery methods can be clinically used depending on the situation. For example, most patients prefer ingestion at night for the prolonged effect, while inhalation is the preferred method during the daytime (Wallace M, personal experience).
Cannabinoid/Opioid System Interactions
With the prescription opioid overdose crisis in the United States, there is concern over the increasing use of medicinal cannabis and its effects on this crisis. Studies have demonstrated that states with medicinal cannabis legalization have actually seen a reduction in opioid analgesic overdose.59 A recent retrospective cross-sectional survey of patients with chronic pain using medicinal cannabis showed a 64% decreased opioid use, decreased side effects of medications, and an improved quality of life.60 In another study of cannabinoid-opioid interaction, 21 subjects with chronic pain taking twice-daily sustained-release morphine or oxycodone inhaled vaporized cannabis three times daily for 5 days. This resulted in a 27% reduction in pain with no altered plasma opioid levels. Pulse oximetry did not show any lowered oxygen saturation suggesting that cannabinoids do not worsen opioid-induced respiratory depression.61
Cannabinoids as Analgesics
There are a limited number of randomized controlled trials involving cannabinoids for the treatment of pain. Stimulated by the burden of chronic pain globally and the need to find safer, nonopioid therapeutic targets, the number of studies has been rising. Complicating this area of research, however, are complex federal regulatory issues because of the Schedule I status of cannabinoids and the lack of standards for cannabinoid form and administration across various studies. The studies differ in the type of cannabinoid (i.e., plant, extract, synthetic), route of administration (i.e., inhalation, ingestion, mucosal absorption), and dosing that create unique challenges in interpretation. All of the current studies have focused on THC. There are no studies focusing on CBD, although there is increasing interest given its lack of psychoactivity. To date, all of the cannabis supplied by the National Institutes of Health that has been used in current studies had CBD levels of less than 1%. A summary of select randomized controlled trials across several pain conditions is highlighted in Table 2.61-75
Risks and Side Effects of Cannabinoids
As with any potential therapy, cannabinoids carry risks and adverse effects. The most common cannabinoid side effects include sedation, dizziness, dry mouth, and dysphoria. Other significant side effects include cognitive impairment, anxiety, and psychosis. It is important to note that most of the published side effects of cannabis and cannabinoids come from the study of their recreational use. A recent study of cannabis for the treatment of chronic pain had no more adverse effects than matched controls.77
The abuse potential of cannabis is controversial. Although cannabis abuse is prevalent, animal studies show that cannabinoids do not seem to be as robust as other agents (e.g., heroin, cocaine, nicotine).78 There appears to be opposing effects of high- and low-dose THC, with high-dose producing aversion and low-dose producing pleasure.79 This therapeutic window has been demonstrated in human studies.80 Plasma levels of THC between 5 and 15 ng/mL appear to be therapeutic for pain relief; however, this relief is lost at levels above 15 ng/mL (Wallace M et al, unpublished data).
With chronic cannabis use, tolerance develops to the physiologic (i.e., cardiovascular) and subjective (i.e., high) effects, and abrupt termination in habitual users will result in withdrawal symptoms similar to opioids. However, withdrawal is less likely to occur or is associated with fewer symptoms when the dose of THC consumed is low.81,82
Regulatory, Professional, and Legal Considerations
Possession and use of cannabis remains illegal under U.S. federal law. Since 1970, cannabis has been listed by the U.S. Drug Enforcement Administration as a Schedule I drug with “high potential for abuse,” “no currently accepted medical use,” and “lack of acceptable safety for use under medical supervision."83 This is in direct contrast to its legal status within many U.S. states for medicinal and recreational use. This has created confusion for many providers and patients.
Neither the U.S. Food and Drug Administration nor any other federal regulatory agency currently oversees or regulates the production and distribution of cannabis or the myriad cannabis-based products sold in medical marijuana dispensaries. Moreover, there is no national oversight, and limited state regulation of the labeling, concentration, dosing, or purity of cannabis and cannabis-based products. Thus, it is often left up to the growers, processors, and distributors of medical cannabis in states where it has been legalized to self-regulate. Lastly, neither cannabis nor any of these products have undergone the large-scale clinical trials necessary for showing clear efficacy for a particular indication. Efforts are emerging to provide better oversight of herbal marijuana processing and distribution.
Marijuana laws vary widely among those states that have passed some form of legalization, and each clinician must be familiar with the state in which they practice. Because marijuana is not approved by the U.S. Food and Drug Administration, no state requires a physician to write a prescription. There has been a push by the American Medication Association to enact federal legislation protecting physicians who prescribe cannabis.
Some states provide guidelines for recommending medicinal cannabis. In the absence of guidelines, clinicians who choose to recommend cannabis should manage their patients in accordance with good medical practice. This involves becoming familiar with the safety and efficacy of medical cannabis and counseling patients on their responsibilities and on the side effects. Patients should then be monitored to assess the clinical effects, adverse effects, and impact on function and quality of life. Appropriate documentation in the patient’s medical record should be made.
CONCLUSION
Cancer pain remains prevalent, yet undertreatment continues, in part due to concerns regarding the use of opioids. The efficacy of opioids in advanced disease has been clearly established, however, questions remain about the safety and effectiveness of opioids in long-term survivors of cancer. As a result of challenges surrounding opioids, alternative analgesics, including cannabis, are being studied. Risks and benefits, as well as regulatory and legal issues, must be carefully considered when recommending these treatment options.
Authors' Disclosures of Potential Conflicts of Interest
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc.
Mike Bennett
Speakers' Bureau: Pfizer
Judith A. Paice
No relationship to disclose
Mark Wallace
Consulting or Advisory Role: Zynerba Pharmaceutical
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© 2017 American Society of Clinical Oncology.
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Published online: October 29, 2018
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Pain and Opioids in Cancer Care: Benefits, Risks, and Alternatives. Am Soc Clin Oncol Educ Book 37, 705-713(2017).
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American Society of Clinical Oncology Educational Book 2017 :37, 705-713
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