JB is a 57-year-old male who presents to the emergency department complaining of acute left-sided chest pain (8/10 on a numeric pain scale) that has been ongoing for approximately 48 hours following a fall at home. He has taken ibuprofen and acetaminophen with no relief. Chest x-ray reveals 3 fractured ribs, and laboratory evaluation is suspicious for multiple myeloma (MM). This diagnosis is later confirmed following bone marrow biopsy, serum protein electrophoresis, and comprehensive laboratory analysis.
Like JB, patients with MM often initially present to medical attention with pathologic fractures due to the presence of widespread osteolytic bone lesions. While the attention of hematology/oncology providers frequently focuses on the diagnosis and management of the patient’s MM, palliation of pain symptoms is a critical concern related to the patient’s quality of life over the short term that must be addressed as quickly as possible, usually prior to the initiation of chemotherapy. Over the natural course of the disease, MM patients often become idealized cases for teaching cancer pain management as many require opioids for acute pain, the use of bisphosphonates in the adjuvant setting for the relief of bone pain and the prevention of skeletal-related events, and management of treatment-induced neuropathic pain resulting from the use of immunomodulatory drugs such as thalidomide or proteasome inhibitors such as bortezomib. As an oncology pharmacist, I am often consulted to make recommendations for the management of the complex and ever-changing pain symptoms that this population experiences. As we assess the needs of the model patient described above, let us also evaluate the management of cancer-related pain in general, focusing on selection of the best medication management and the application of clinical practice guidelines.
Acute Pain Management
Pain associated with cancer is one of the chief complaints of patients, affecting their quality of life. It has been estimated that as many as 50% of all cancer patients experience pain during treatment. Pain is more commonly associated with metastatic disease and end-of-life scenarios, yet it frequently requires medical intervention even in patients with early-stage disease treated with curative intent.1,2 For patients with acute pain management needs, the World Health Organization (WHO) algorithm has historically served as a reference for initiating therapy. Utilizing a strategy by which pain management is escalated based on the patient’s self-report of pain intensity, objective physical assessment, and the patient’s history of opioid and non-opioid drug therapy, this algorithm attempts to appropriately tailor the selection of initial analgesic medication in an individualized manner.3 In the case of JB, a pain level of 8/10 on a numeric rating scale would be classified by WHO criteria as moderate/severe pain. Assuming that JB is opioid-naive, the WHO pain ladder recommends initiation of therapy with a short-acting opioid such as hydrocodone or oxycodone.
In this case, hydrocodone-acetaminophen 5 mg/500 mg was selected, and JB is counseled to take 1 to 2 tablets every 4 to 6 hours as needed.
From a patient education perspective, it is important to recognize that these commonly used administration instructions for hydrocodone-acetaminophen products could result in a patient consuming 6 g of acetaminophen in a 24-hour period, thus exceeding the 4-g daily maximum dose, which could lead to hepatic injury. As such, patients and caregivers should be appropriately educated on how to responsibly use these medications and what adverse events can be reasonably expected. In addition to dosing and administration directions, patients beginning opioid-based pain management regimens, like JB, should also be educated on the risk of drowsiness, nausea, and constipation. In our practice, patients prescribed opioid pain medications are strongly encouraged to concurrently take a mild laxative such as senna or polyethylene glycol 3350 and a stool softener such as docusate to prevent constipation from becoming a serious medical issue.
While this patient case serves to illustrate the application of WHO recommendations for initiation of pain management in the moderate/severe setting, the WHO also provides guidance for the management of mild and severe pain. For mild pain, practitioners are encouraged to recommend nonpharmacologic treatment options including heat, cold, massage, and music, as well as over-the-counter (OTC) alternatives such as acetaminophen and nonsteroidal anti-inflammatory drugs such as ibuprofen or naproxen. Conversely, in the setting of severe pain, the WHO recommends stronger opiates including morphine, fentanyl, and oxycodone. Critics point out that the stepwise approach of beginning with milder treatment options, including OTC analgesics, and escalating based on the level of relief delivered by these treatments is often unsuccessful in gaining patients meaningful pain relief in a rapid manner. In fact, many publications have argued for revisions to the WHO pain ladder to include the addition of new levels incorporating surgical interventions such as the implantation of pain stimulators, which may offer significant relief to patients suffering with chronic pain not relieved with traditional medication-based approaches. Clinicians should also be aware that clinical practice guidelines for the mitigation of cancer-related pain are available from the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology.4,5 These organizations provide evidence-based approaches to the management of these patients that are often comprehensive and account for nuances in patient care not addressed by the older WHO program.
Adjuvant Pain Management Strategies
A nuclear medicine bone scan reveals that JB has osteolytic bone lesions throughout his thoracic spine, left ribs, and the distal head of the left femur.
In this case, it is apparent that JB’s acute pain has resulted from the fracture of 3 ribs on the left side. While opioid analgesics are often relied on as the cornerstone of therapy for acute pain, no intervention has yet been made for this patient’s bone lesions and, in particular, to reduce his risk of future fracture and corresponding quality-of-life concerns, including mobility and pain. Though not typically classified as analgesics, in this setting bisphosphonates have become a commonly used adjuvant treatment. In a study of 377 patients with MM, Berenson and colleagues demonstrated an increase in the time to first skeletal event in those patients treated with pamidronate. Additionally, bone pain and quality of life were significantly improved in those patients receiving pamidronate versus placebo. Similar results have been observed with zoledronic acid. As a result, both are described in the NCCN clinical practice guidelines for MM as highly recommended for all MM patients with symptomatic disease.6-9 Some practitioners may inquire about the use of denosumab in this patient population. Currently, denosumab is not recommended as an alternative to bisphosphonate therapy in MM patients because an increased risk of mortality was observed in this patient population in a post hoc analysis of a large phase 3 clinical trial evaluating the efficacy of zoledronic acid versus denosumab. Ongoing clinical trials are attempting to address this question prospectively.10 Bisphosphonates are also indicated by NCCN guidelines for similar end points of pain relief and prevention of skeletal events in other malignant diagnoses, including breast and prostate cancer.11,12
The decision is made for JB to begin zoledronic acid 4 mg q28 days following laboratory analysis to ensure appropriate renal function.
Clinicians are encouraged, and pharmacists should be watchful, to ensure that patients started on bisphosphonates have adequate renal function. For patients with some degree of renal impairment, specific recommendations are available for dose reduction based on creatinine clearance. Additionally, patients should have a dental assessment conducted as part of their physical exam to ensure that they do not have unresolved jaw, tooth, or gum issues that may increase their risk of developing osteonecrosis of the jaw, a serious but rare adverse event of these types of therapies.
In addition to bone-targeted therapies, patients may require any number of other adjuvant analgesics that may include antidepressants, muscle relaxers, corticosteroids, neuroleptics, psychostimulants, topical analgesics, etc.13 Clinicians are encouraged to recognize that classic analgesic medications may lead to a greater degree of pain relief in those patients in whom adjuvant therapies are appropriately utilized.
For patients diagnosed with MM, immunomodulatory drugs and proteasome inhibitors will almost certainly play a role in their treatment and, thus, these patients are all too often left with neuropathy induced by these medications. Currently, a number of medications are used to alleviate neuropathic pain associated with chemotherapy, including tricyclic antidepressants, anticonvulsants (gabapentin and pregabalin), and opioids. Concerns of neuropathy are not exclusive to the management of patients with MM. Patients treated with taxanes (docetaxel and paclitaxel) and platinum analogs (cisplatin, carboplatin, and oxaliplatin) also are likely to experience this adverse event, and practitioners should be prepared to intervene if neuropathies begin to limit activities of daily living.14 In our practice, we have come to favor pregabalin for initial management of neuropathies because, in contrast to gabapentin, it does not require dose titration, is well tolerated, and has been reported to reduce the impairment of sensation in the hands and feet often experienced by these patients. However, I caution that often the best treatment of chemotherapy-induced neuropathy is time. While medications may have some limited impact on the symptoms patients experience, substantial time, measured as months to years, is required for nerve regeneration and return of sensation.
To date, JB’s MM is in remission following hematopoietic stem cell transplantation and maintenance lenalidomide. He continues to receive monthly infusions with zoledronic acid, but his other pain symptoms have resolved completely.
While this exercise in cancer pain management is not intended to be a comprehensive review of clinical practice guidelines, I hope it serves to illustrate the clinical decision making pertinent to the role of an oncology pharmacist for a representative patient with cancer. Providers, including oncology pharmacists, should completely review the medical record, radiographic scans, and laboratory values of patients with cancer to create an appropriate care plan for pain management. Focus must be placed not only on the patient’s acute complaints but also on the recognition that medical intervention, including chemotherapy, may induce other issues that will ultimately affect the patient’s experience of pain and quality of life. In this case, the oncology pharmacist is a key member of the healthcare team, often responsible for appropriate medication selection, dose adjustment based on organ function, adverse event monitoring and prevention, and patient education.
Finally, as healthcare providers, we must remember that patients desire adequate pain relief that fits their lifestyle and allows them to pursue, to the best of their ability, the things that bring them joy. While it may be clinically appropriate to identify a goal of reducing the patient’s self-report of pain intensity from an 8 to a 4 (on a 10-point scale), this may not allow the patient the freedom from pain to live a life filled with quality. Rather, I prefer the idea of identifying 1 or 2 things that pain has prevented a patient from achieving and use these tangible objectives to establish pain management goals. Ultimately, pain management in the setting of oncology is a complex, multidisciplinary problem that allows opportunities for input from various healthcare providers with congruent goals for the relief of pain that could be debilitating, not only to the patient, but also to family and caregivers.
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9. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Multiple Myeloma. Version 1.2013. www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed February 25, 2013.
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11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Breast Cancer. Version 1.2013. www.nccn.org/professionals/physician_gls/f_guidelines.asp#breast. Accessed February 25, 2013.
12. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Prostate Cancer. Version 1.2013. www.nccn.org/professionals/physician_gls/f_guidelines.asp#site. Accessed February 25, 2013.
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