1. Dietrich, Brian MD
  2. Ramchandran, Kavitha MD

Article Content

Patients with cancer experience a multitude of symptoms. Among these, pain is the most frequent and distressing symptom encountered. In one meta-analysis, nearly 60 percent of patients undergoing anti-cancer therapy reported pain, with 64 percent of these having advanced disease and the remainder receiving treatment with curative intent (Ann Oncol 2007;18:1437-1449). Even at the end of life, it is estimated that 25 percent of patients will die in severe pain.

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Despite this high prevalence, studies have demonstrated that pain frequently remains underdiagnosed and inadequately treated (Lancet 2001;357:1311-1315). When left untreated, severe pain permeates through all aspects of the patient's life, leading to significant psychosocial distress and poor quality-of-life. Further, there is growing evidence that effective palliation of symptoms, such as pain, has an impact on survival (N Engl J Med 2010;363:733-742). Given the importance of appropriate management, pain should be addressed as part of the overall treatment plan.


Assessment of Cancer-Related Pain

When should pain evaluations occur and what are the most important features to include in these evaluations?


Given the frequency of pain issues in oncology, all reports require further investigation. NCCN guidelines recommend that pain assessments take place at the initial evaluation, at each subsequent encounter, and whenever new therapy is implemented, with more in-depth assessments performed should pain be identified. Pain can be broken down into subtypes based on pathophysiology (nociceptive vs. neuropathic) or temporal relation to onset (acute vs. chronic), and a good history can help key a clinician into when urgent intervention is needed for acute issues, such as disease processes resulting in obstruction, perforation, infection, pathologic fracture, or cord compression.


When present, pain should then be quantified using a numerical rating or established categorical scale (Pain 1995;61:277-284), which also can be used as a baseline value to assess responsiveness to any intervention employed. Secondly, an estimate of how much the pain is interfering with daily function should also be gauged (Pain 1996;67:267-273). Finally, goals and expectations of the treatment plan should be discussed with the patient and family. The endpoint of any comprehensive pain assessment should yield the etiology and pathophysiology of the pain, and exclude pain related to an oncologic emergency that requires urgent attention.


Management of Cancer-Related Pain

What is the initial treatment approach for the opioid-naive patient? What is the expected success rate for these initial management strategies?


The WHO has a frequently utilized strategy in the pharmacologic treatment of pain, which proposes a three-step analgesic "ladder" in the initial pharmacologic management strategy. Though first made available in 1986, these guidelines continue to be a gold standard in pain control, and helped legitimize the use of opioids in treating cancer pain while promoting teaching campaigns for managing pain and the side effects for analgesics (Can Fam Physician 2010;56(6):514-517).


Initial treatment should include prompt administration of orally administered analgesics and consideration of adjuvant therapies based on pain history. For mild pain (score 1-3) in patients not on any form of analgesics, NSAIDs or acetaminophen can be utilized, with titration of short-acting opioids for pain that is not relieved with these initial measures. To increase chance of efficacy, drugs are best given in a scheduled fashion, often every 4-6 hours, rather than on demand. When short-acting opioids are being started, frequent initial doses are 5-10 mg of an immediate release formulation, with rate of titration dependent on the severity of pain on presentation (moderate vs. severe), with shorter interval reassessment in patients with higher pain scores.


For chronic, persistent pain controlled with stable doses of short-acting opioids, long-acting formulations with as-needed break-through doses for rescue can be provided. Implementation of these initial strategies are thought to be effective in 70-90 percent of cases, though the remaining 10-30 percent may suffer from refractory pain that remains undertreated (Can Fam Physician 2010;56(6):514-517).


What are some key factors that put patients at risk for undertreatment or barriers to cancer pain management?


Despite a high frequency and multiple treatment options, studies have demonstrated that pain frequently remains underdiagnosed and inadequately treated (Lancet 2001;357:1311-1315). A number of risk factors have been identified that contribute to this phenomenon, from causes related to patient, provider, and the health care system. Patient factors include age, gender, cultural and language barriers, education level, and cognitive impairment.


Uncontrolled pain is more often reported in patients over age 65 (Am J Hosp Pall Care 2003;20:140-141). Women tend to report higher pain scores and lower satisfaction, with lower adherence, more often stopping medication when their pain improved (Clin J Pain 2008;24:627-636). Minority cultural groups tend to have a higher probability of having suboptimal pain control through a number of barriers, including lack of belief that their pain could be adequately addressed and concern of developing addition to prescribed medications, which may be more pronounced in this group. Patient beliefs can result in their undertreatment, with some reluctant to bring up pain concerns due to feelings of hopelessness that little can be done about their pain(Support Care Cancer 2001;9:148-155). Financial barriers can exist as well, and can be difficult for patients to bring up.


Health care providers may undertreat for any number of reasons. Some may not correctly interpret the severity of pain and the impact it may be causing. Clinicians may fail to investigate or believe in reported pain. Time constraints in a busy clinic are another issue, with less time sometimes given to symptom assessment than other treatment concerns. Systems barriers are becoming more frequent as well, with greater restrictive state and federal prescribing practices in a nation where opioid abuse has become more common. Consideration of the barriers that exist is the first step in trying to bypass them.


Treating the Opioid Refractory Patient

When pain continues to be severe despite initiation of opioid medications, what are some additional pharmacologic therapies that are available?


Though most frequently used for mild to moderate pain, non-opioid analgesics such as Tylenol and NSAIDs can be used to augment effects of opioid medications. In one randomized controlled trial (RCT) in patients with continued pain due to bony metastasis already on opioids, patients were given either oxycodone at 5 mg in combination with 325 mg of acetaminophen every 6 hours for 3 days. In the treatment arm, pain scores and the need for rescue medications was reduced, though the study design did not permit for assessment of the relative contribution of each agent to be determined (J Clin Pharm Ther 2012;37(1):27-31).


Corticosteroids can provide adjunctive benefit for a variety of inflammatory and neuropathic processes when added to an opioid regimen. They have a specific role in the patient with bone metastasis causing cord compression. When neuropathic symptoms are present, there is supportive evidence for use of a number of antidepressants as adjuvant analgesic agents. Tricyclic agents and SNRIs have the strongest evidence for their analgesic properties independent of effects on mood (Turk J Cancer 2004;34(3):24-31). Though more frequently used to aid in sleep and stimulate appetite, mirtazapine has been described to have some benefit in cancer pain as well (J Pain Symptom Manag 2002;23(5):442-447). Each of these adjunct agents have their own side effects such as additional sedation or anti-cholinergic effects that should be considered before prescribing.


What are some interventional strategies that have been shown to be beneficial for difficult to treat pain, or in patients unable to tolerate opioid medications?


Interventional procedures include neurolytic blocks, regional infusion of analgesics, and neurostimulation procedures. About 70-80 percent of pancreatic cancer patients report severe abdominal pain (Pain Physician 2005;8(3):291-296), resulting from high rates of invasion into the nearby celiac plexus.


In a meta-analysis of seven RCTs evaluating the benefit of celiac plexus blocks (CPB), better pain scores and reduced opioid use were noted at 4 weeks but not 8 weeks following the intervention, suggesting a benefit though durability may be an issue (Pain Pract 2014;14(1):43-51).


Case reports for endoscopic ultrasound-guided techniques to perform CPB have noted positive impact on pain scores lasting up to 12 weeks (Pain Med 2013;14(8):1140-1163). Transient diarrhea and hypotension are the most frequent side effects reported.


Neuraxial analgesia involves delivery of anesthetics, opioids, or combinations into the epidural space through a catheter. The goal of this delivery system is to provide pain relief at much lower doses to minimize toxicity. This type of therapy may have a role in the patient with confusion, excessive sedation, and/or inadequate pain control with oral medications (Br J Anaesth 2008;101(1):95-100). For patients with neuralgias or complex regional pain syndromes, neurostimulation procedures such as spinal cord stimulation may be considered, though exact benefit is difficult to determine given the small sample sizes in studies (Support Care Cancer 2016;24:1429-1438). As with any procedure, caution should be taken in patients requiring anticoagulation.


Bone metastasis are a frequent source of refractory cancer pain. Are there any special considerations that can be considered for this group?


Patients with bony disease can have debilitating symptoms, and are at greater risk for unique skeletal complications referred to as skeletal related events (SREs). SREs refers to an assemblage of potential complications, including pathologic fracture, need for surgical intervention or radiation, and spinal cord compression. Agents such as bisphosphonates and RANKL inhibitors are primarily administered given their well-established role in reducing SREs. Beyond this role, numerous clinical trials demonstrated evidence for the analgesic effects from bone strengthening agents in a number of tumors, both from bisphosphonates and denosumab (Pain 2004;111:306-312, Cancer 2013;119:832-838, Can Urol Assoc J 2012;6(6):465-470).


Surgery and radiation therapy can be performed to provide stabilization and prevent impending fractures or further neurologic complications. Cement fixation of malignant disease involving the bone causing fracture, with vertebroplasty and kyphoplasty being the most common techniques, has been used in recent years (Ann Oncol 2011;22(4):782-786). In vertebroplasty, cement is injected directly into the vertebral body to cause stabilization. In kyphoplasty, a balloon creates a space in the vertebral body, into which cement can be injected to restore some height to the compressed vertebral body. In one meta-analysis of 30 studies (including one RCT and seven prospective studies) including 987 participants, approximately half of the studies noted a reduction in pain, though high-quality research is limited and complications such as spinal cord compression and osteomyelitis can occur, with an estimated incidence ranging from 0-29 percent reported (Clin Radiol 2011;66(1):63-72).


Advanced disease can occur with a multitude of concurrent physical and psychological symptoms that can become difficult for the treating physician to manage alone. What consultative services are available to help assist in the treatment of these patients?


Specialty consultative services can help in the management of a multitude of physical and social issues that may arise. Palliative care, social work, spiritual care, physical/occupational therapy, psychiatry, and pain management services are all considerations for referral when a need is identified and when additional evaluation is felt to lead to alleviation of a physical or psychosocial symptom or will help patients become more functional in their daily activities. Using a collaborative approach with integration of these services at different times throughout a patient's course can provide more effective strategies in managing difficult to treat symptoms.


BRIAN DIETRICH, MD, is a fellow in Hematology/Oncology, and KAVITHA RAMCHANDRAN, MD, is Clinical Assistant Professor, both at Stanford University School of Medicine, Stanford, Calif.

Brian Dietrich, MD. ... - Click to enlarge in new windowBrian Dietrich, MD. Brian Dietrich, MD
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