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14 Articles in Volume 18, Issue #2
Ask the Expert: Is there evidence to prescribe cyclobenzaprine long-term?
Challenging the Chronic Pain Personality Profile
Designer Peptide May Prevent Chemo-Induced Neuropathy
Inside the Cancer Pain Research Consortium
Intrathecal Drug Therapy for Cancer-Related Pain
Managing Cancer Pain in an Era of Modern Oncology
Mapping Complex Pain: A Case Study
Medication Overuse Headache: Inaccurate and Overdiagnosed
Pain and Fall Risk in the Elderly
Reporting Quality of Care in Cancer Pain Management
Sharing the Risk: An Update to DEA & Doctors Working Together
The Intensifying Conflict Between Opioid Control and Pain Control
Two Mobile Apps Aim to Target Patient Compliance & Safety
Why Prescribers Need to Adopt Abuse-Deterrent Opioids

Managing Cancer Pain in an Era of Modern Oncology

A review of current, evolving, and needed strategies for treating cancer patients living with chronic pain

The recent decade brought significant advances in the treatment of cancer which, in turn, had profound effects on the clinical practice of oncology. Two out of three people diagnosed with cancer can now expect to live at least 5 years after diagnosis and many live with cancer as a chronic disease. Unfortunately, despite more than three decades of advocacy and efforts directed at improving cancer pain management worldwide, it is still quite prevalent, often poorly managed, and remains one of the most feared aspects of the disease.

There were an estimated 1.7 million new cases of cancer in 2017, according to the American Cancer Society. More than half of the patients who will go on to receive anticancer treatments and two-thirds of the patients whose disease will become advanced or metastatic will suffer from cancer-related pain.1 A vast majority of patients with cancer will require opioids, which, to this day, remain the most effective means of relieving moderate to severe cancer pain. However, new findings related to the effects of long-term exposure to opioids and its many potential adverse effects, including substance abuse and misuse, have raised questions about what may be the best and safest approach going forward to manage cancer-related pain.

As the rates of cancer survivorship continue to climb, primary care physicians and specialists outside of oncology (eg, palliative care practitioners, psychiatrists, physical medicine and rehabilitation specialists, and interventional pain physicians) might become increasingly involved in the management of pain in cancer patients. This article summarizes common approaches and strategies for the management of cancer pain in this new era of oncology.

What is Cancer Pain?

Neoplasm-induced pain is a complex biological phenomenon that involves diverse neurophysiological changes; it is characterized by significant affective, cognitive, and sociocultural response. This paper focuses on cancer pain that is caused directly by the neoplastic processes, with the understanding that pain in patients with cancer is often complex, involving multiple etiologies, and different pathophysiologies. For example, pain in a patient with advanced cervical cancer may involve somatic/neuropathic pain related to the pelvic mass, complicated by local side effects of radiation therapy, painful peripheral chemo-induced neuropathy (see Designer Peptide May Prevent Chemo-Induced Neuropathy for research being done in this area), and chronic mechanical back pain that is now exacerbated by the patient’s limited mobility.2

The Evolution of Cancer Treatment Strategies

Pain management in cancer patients requires an individualized and multimodal plan of treatment that incorporates pharmacological, interventional, rehabilitation, and behavioral approaches. After treating the cancer itself, the goal becomes improving the patient’s quality of life while minimizing pain and effectively managing potential side effects of the treatment. Achieving this balance is often difficult and requires time, perseverance, and close collaboration among the clinicians, the patient, and his/her caregivers.

The current era of cancer pain management began in the mid-1980s, with the creation of the World Health Organization’s (WHO) analgesic stepladder.3 Prior to its launch, most patients with cancer were dying in uncontrolled pain. The stepladder approach marked a significant achievement, providing a simple but systematic approach to the treatment of pain in patients with advanced cancer. The ladder also helped to destigmatize and legitimize the use of opioids for patients with cancer.

Fast-forward to the 2010s, and thanks to significantly improved rates of survivorship, many patients live with cancer as a chronic disease. Many also suffer from chronic pain related to their cancer or cancer treatments and, therefore, remain on opioid regimens for extended periods of time, and, in some cases, for the remainder of their lives. New, safe, and effective approaches to treating chronic cancer pain are needed. Unfortunately, despite the advancement of many potential compounds in preclinical studies (most of which target anti-nociception), no new class of analgesics has been developed and opioids remain the cornerstone of cancer pain management.

Current Cancer-Pain Treatments

Opioids

Results of a recent analysis of Cochrane reviews (152 studies, including 13,524 patients) concluded that there is evidence to state “19 out of 20 people with moderate or severe pain who are given opioids and can tolerate them should have that pain reduced to mild or no pain within 14 days.”4 The review also noted that 1 to 2 out of 10 patients treated with opioids developed intolerable side effects (typically nausea and constipation) that required a change in therapy.

Morphine is the oldest opioid used and is still considered a gold standard in cancer pain management. The existing evidence does not suggest the superiority of any particular opioid, and many are used in clinical practice including tramadol, oxycodone, hydromorphone, fentanyl, buprenorphine, tapentadol, and methadone. The majority of these medications are administered orally, although transdermal formulations (fentanyl and buprenorphine) may be beneficial in patients who have difficulty swallowing or problems with gastrointestinal absorption. The literature and clinical practice indicates that most cancer patients benefit from using extended-release formulations of opioids that minimize frequent dosing.

In cases of severe cancer pain, or pain in terminally ill patients, subcutaneous or intravenous opioids may be used, including in an at-home setting if needed via patient controlled analgesia pumps. Additionally, for patients with intractable pain who have failed to respond to standard therapy and patients whose narrow therapeutic window makes the use of conventional therapies unacceptable, the infusion of opioids via epidural or intrathecal space may be utilized. The use of the epidural route is typically reserved for patients with a life expectancy of days to weeks, as long-term use of epidural infusion has been associated with higher incidence of side effects and catheter-related problems. An option that remains underutilized is the use of implantable intrathecal pumps. These pumps have been around since 1982, however, due to multiple barriers, including price, patients’ reluctance to undergo the implantation procedure, and relatively poor familiarity of this technology among oncologists, broader implementation has been challenging5 (see Intrathecal Drug Therapy for more details).

Just as cancer management strategies have been evolving, the role of opioids in cancer pain treatment has been changing as well, principally due to an understanding of potential adverse effects associated with their chronic use (eg, hypogonadism, mood disorders, sleep-disordered breathing, cognitive impairment). To complicate matters, however, many cancer patients are older, suffer from multiple comorbid illnesses, and are taking multiple medications. It is often challenging, therefore, to find the proper balance between effective analgesia and the risks associated with opioid therapy in these patients.

Nevertheless, poorly managed cancer pain has been associated with significant impairment of a patient’s quality of life and may further hinder the patient’s ability to tolerate anticancer treatments.

Co-Analgesics

Many patients with cancer suffer from neuropathic pain, which is more challenging to treat than nociceptive pain and strongly associated with worsened quality of life. Effective treatment often requires the use of co-analgesics, such as gabapentinoids, tricyclic antidepressants, and serotonin and norepinephrine reuptake inhibitors (eg, duloxetine or venlafaxine). Additionally, acetaminophen and nonsteroidal anti-inflammatory drugs may be helpful, although their use is limited by their toxicity, especially in cancer patients whose liver, kidney, or bone marrow function may be affected by their disease or antineoplastic treatments.7

Cognitive Behavioral Therapy

Developed in the 1960s, cognitive behavioral therapy has been well established as a technique useful in the management of pain, including cancer pain. By restructuring negative thought patterns and emotional responses, patients may experience less pain catastrophizing, improved resilience, and better pain tolerance.8,9

Opportunities for Novel Analgesics & Approaches

There are several potential new targets for treating cancer pain. One area that may, in fact, lead to the discovery of new opioid analgesics with improved tolerability is related to molecular discoveries of opioid action. For example, TRV130 is a novel ligand that produces analgesia with no severe side effects and tolerability similar to that of morphine.10 IBNTxA is another compound that may mediate potent analgesia with significantly less risk of respiratory depression and gastrointestinal or drug-liking effects.11 The intensity of pain sensation shows diurnal variations, with the lowest perceived variation during dark hours. This discovery led to studies examining the use of melatonin for treatment of pain, which seems to exert analgesic properties by acting on the MT2 receptor located in the dorsal horn of the spinal cord and in multiple areas of the central nervous system.12 Quetiapine is an atypical antipsychotic used to treat some psychiatric conditions that also has shown potential analgesic properties in animal models of cancer-induced bone pain.13

Cannabinoids

Cannabinoids have been used for the treatment of pain for centuries. However, there is very scant evidence surrounding their effectiveness in relieving cancer pain. Two recent randomized controlled trials14 using nabiximols (oromucosal spray of whole cannabis plant extract with a 50:50 mixture of tetrahydrocannabinol and cannabidiol) showed modest benefit when used in addition to opioids in patients with chronic cancer pain.

A recently published critical review15,16 showed that the use of inhaled cannabis might be beneficial (1 in 5 to 6 patients reported benefit) for the treatment of neuropathic pain. Additionally, there is evidence that some patients with pain may be able to taper their opioid use when taking cannabis. Not surprisingly, there is growing interest among the public but also in the pain community regarding potential applications of medical marijuana for the treatment of pain.

Neuromodulation

Neuromodulation is a rapidly evolving field that encompasses a set of treatment techniques that achieve analgesic effects by electrically or chemically altering signal transmission within the central nervous system. Modalities such as spinal cord stimulation and neuraxial analgesia have been in practice for quite some time. Others, such as peripheral nerve stimulation, scrambler therapy, deep brain stimulation, transcranial direct current stimulation, or motor cortex stimulation have yet to be fully examined in the cancer pain management setting. It seems, however, that noninvasive techniques, if proven effective in clinical trials, may become important nonpharmacological modalities in the treatment of cancer pain.17,18

Conclusion

In the 1960s, modern hospice movement founder Cicely Saunders coined the term “total pain” to illustrate the complexity and multidimensional nature of the pain experience in cancer patients. To this day, her simple yet profound holistic concept of pain holds true. And yet, despite tremendous progress in many areas of oncology, cancer pain remains a challenging clinical problem. To advance the management of cancer pain effectively, we need a new and expanded paradigm of treatment that incorporates novel ways of treating pain that focus not only on the nociception but also on the emotional and cognitive aspects of cancer pain in a comprehensive and patient-centered way.

Last updated on: April 12, 2019
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