US Pharm. 2014;39(3):44-47.

 

ABSTRACT: Cancer pain is one of the most difficult supportive care issues to manage, as it is subjective. Many physicians struggle with outpatient management of cancer pain in adults, and pharmacists can play a key role in recommending agents, titration, and conversions. Another area in which pharmacists are essential is managing adverse effects associated with pain medications. An important aspect of pain management is breakthrough cancer pain, which is also an area for improvement. Studies have shown that appropriate management of pain in oncology patients can significantly increase quality of life and eventually overall survival.

Pain is one of the most common symptoms cancer patients experience. It is defined as “an unpleasant multidimensional, sensory and emotional experience associated with actual or potential tissue damage or described in relation to such damage” by the International Association for the Study of Pain.1 Cancer pain has many different causes, including advanced disease, neuropathy, bone weakness or invasion, infection, postoperative effects, growth factors, and chemotherapy.2 Pharmacists play a major role in oncologic pain management, whether it is advising inpatients during physicians’ rounds, counseling patients at an infusion center, or advising patients on OTC pain medications at a community pharmacy.

There is a substantial amount of evidence that links survival in oncology patients to pain control, and undertreatment of pain has been documented in various clinical settings.1 However, pain is a subjective phenomenon, which makes it difficult to assess patients accurately because it requires reliance on the patient’s self-assessment using pain scales. If pain in cancer patients is not adequately controlled, it can lead to functional impairments such as decreased activity, sleep disturbances, loss of appetite, and an overall decrease in quality of life.3

There are quite a few barriers to cancer pain management, which make it difficult to attain proper pain control. Healthcare professionals sometimes do not have adequate knowledge of pain management or, at times, do not perform a complete pain assessment. Sometimes, patients and family members are reluctant to report pain due to myths and misconceptions about opioids. Other times, there are barriers with the healthcare system regarding reimbursement.2 Because of poor pain management in cancer patients, it is evident that more pain management awareness is needed for healthcare professionals.

Pain Assessment Scales

All patients should be asked to rate their pain on a scale of 1 to 10 every time they arrive for a checkup, and scheduled reassessments should be performed in addition to asking the patient to describe his or her pain for a subjective measurement.1 A common scale used for adults is the Wong-Baker FACES Pain Rating Scale, which is also a particularly useful tool for children over the age of 3 years and for those who may have a language barrier because it uses pictures (FIGURE 1).4



The World Health Organization (WHO) has developed a three-step ladder based on the pain scale for treatment options (FIGURE 2).5 Step 1 on the ladder is mild pain, step 2 is moderate pain, and step 3 is severe pain. On a scale from 1 to 10, if the pain is rated from 1 to 3 (mild pain), it is suggested to start with acetaminophen, aspirin, or nonsteroidal anti-inflammatory drugs (NSAIDs) for all types of pain levels. If the score is 4 to 6 (moderate pain), it is suggested to add a mild opioid (e.g., tramadol or codeine). If the score is 7 to 10 (severe pain), it is suggested to add a strong opioid (e.g., morphine, hydromorphone, fentanyl, methadone, or oxycodone).6 It is always better to titrate pain medications according to response and to have a long-acting agent as well as a drug needed just for breakthrough pain.1


Treatment of Cancer Pain

Mild Pain: Mild pain should first be treated with nonopioids such as acetaminophen, ibuprofen, naproxen, or celecoxib. Additional choices include other NSAIDs (e.g., diclofenac, etodolac, fenoprofen, indomethacin, meloxicam, ketoprofen). However, aspirin should be avoided in cancer patients due to its irreversible antiplatelet effects. OTC NSAIDs should be used first (e.g., ibuprofen, naproxen) before trying high-strength prescription NSAIDs.1

The use of acetaminophen and NSAIDs can be limited during myelosuppressive chemotherapy because of its antipyretic actions. It is vital to educate patients to take additional care when monitoring their temperature; otherwise, it will be more difficult to determine if a patient has a fever or not. Acetaminophen should also be used with caution in patients receiving chemotherapy that could cause hepatotoxicity, such as anthracyclines (e.g., doxorubicin, daunorubicin, idarubicin, epirubicin) and vinca alkaloids (e.g., vincristine).6

Although not as problematic as aspirin, NSAIDs should be used with caution due to their thrombolytic effects. They should also be used with caution in patients at risk for renal toxicity, particularly those who are >60 years of age, are taking concomitant nephrotoxic chemotherapy agents such as cisplatin, or have compromised fluid status, interstitial nephritis, or papillary necrosis. If the blood urea nitrogen (BUN) or serum creatinine (SCr) doubles from the baseline BUN/SCr (normal range is 7-20 mg/dL for BUN and 0.6-1.1 mg/dL for SCr) or hypertension worsens, then the NSAID should be discontinued. NSAIDs should be used with caution in patients who have a history of gastrointestinal (GI) problems and peptic ulcer disease. Adding a proton pump inhibitor (PPI) or histamine-2 (H2) receptor antagonist should be considered.6

Cyclooxygenase-2 (COX-2) inhibitors such as celecoxib have the same restrictions in cancer patients. They should be used with caution in patients with GI problems and those on chemotherapy who are nephrotoxic. COX-2 inhibitors have increased thrombotic potential, which leads to an increased risk of hypertension and stroke. Oftentimes, use of COX-2 inhibitors is limited due to cost and reimbursement issues. For mild pain, the first-line treatment would be ibuprofen, then another type of NSAID, then acetaminophen.1

Moderate Pain: For moderate pain treatment, mild opioid agonists should be used. These include codeine 15 to 30 mg po or IM every 3 to 4 hours, hydrocodone/acetaminophen 5 to 10 mg/325 mg po every 3 to 4 hours, and tramadol IR (immediate release) 50 to 100 mg every 4 to 6 hours or tramadol ER (extended release) 150 to 600 mg po daily. Codeine and tramadol are both available as single agents or in combination with acetaminophen.7 Hydrocodone as a single agent was approved by the FDA in October 2013 at 10 mg po every 12 hours for severe pain, but its use is controversial due to abuse. To minimize this, the FDA has put hydrocodone in a Risk Evaluation and Mitigation Strategy (REMS) program and is planning on conducting a postmarketing study to evaluate serious risks with long-term use.8

Some common adverse reactions for all three drugs are nausea, vomiting, constipation, dizziness, drowsiness, and sweating. Tramadol should be used with caution in cancer patients who are also taking a tricyclic antidepressant or a selective serotonin reuptake inhibitor (SSRI) for depression because of the increased risk of serotonin syndrome. Since tramadol is a weak mu receptor agonist and serotonin uptake inhibitor as well as a norepinephrine inhibitor, it may have some role in the management of neuropathic pain in oncology patients.1

Severe Pain: Severe pain should be treated with a nonopioid agent first, and if that fails, a strong opioid agonist should be used (dosage depending on whether the patient is opioid naïve), such as morphine 15 mg po/IM/SC/PR or 5 mg IV; oxycodone 10 mg po; oxymorphone 5 mg po/IM/SC/PR or 0.5 mg IV; hydromorphone 4 mg po/IM/SC/PR or 0.75 to 1.5 mg IV; fentanyl 25 to 100 mcg transdermal patch or 50 mcg IV; or methadone 2.5 to 10 mg po. Morphine, oxycodone, and oxymorphone are all available in the immediate and sustained-release forms. Morphine is known to be the gold standard for opioids in cancer pain but should be used with caution in patients with renal and hepatic dysfunction.1

An analgesic to avoid in cancer patients is meperidine. It has metabolites that can accumulate in the kidneys, and for patients with renal dysfunction, it can potentiate seizure activity. If absolutely necessary, meperidine may be used for intermittent pain in theses patients.1

All opioids have common adverse effects, but for cancer patients who are already experiencing side effects from chemotherapy, these can be troublesome. The most common is constipation, which can be managed by docusate and senna OTC. Nausea from opioids can be managed with metoclopramide, promethazine, or 5-HT3 receptor antagonists. Initially, patients can be very sedated from either the opioids or metoclopramide, but this will usually subside in 3 to 7 days. Another adverse effect is delirium, but sometimes in oncology patients delirium may result from central nervous system (CNS) metastases. Respiratory depression is more common with more potent opioids, and bladder spasms are more common with longer-acting agents. If any of these adverse effects persist for more than a week, then consider switching to another opioid (i.e., opioid rotation).1

Bone Pain

One of the most common types of pain that oncology patients feel is bone pain.1 This can be a consequence of metastases or the use of granulocyte-colony stimulating factors like pegfilgrastim or filgrastim. If the bone pain is due to tumor growth, this can cause other complications such as hypercalcemia, anemia, spinal cord compression, and decreased mobility, all of which affect the quality of life of the patient. Since growth factors like pegfilgrastim and filgrastim work in the bone marrow to produce more white blood cells, pain can result in patients taking these medications. Pegfilgrastim is given as a one-time dose. Filgrastim is given once a day for 7 to 10 consecutive days. If the pain becomes unbearable, the physician may recommend splitting the doses and using filgrastim instead of a one-time dose of pegfilgrastim, which may cause more bone pain. The downside is that this requires daily administrations at home by the patient or the patient’s caregiver.1

With regard to pharmacologic treatment, bisphosphonates (e.g., ibandronate, pamidronate, zoledronic acid) are used first-line in combination with opioids for bone pain. NSAIDs or glucocorticoids are used in patients with opioid-refractory bone pain.1

Breakthrough Cancer Pain

Breakthrough cancer pain (BTCP) is another common adverse effect incurred by oncology patients. It is defined as “transient pain exacerbations among patients with stable and controlled basal pain.”9 The American Pain Foundation has reported that it occurs in up to 90% of these patients.9 BTCP can affect one’s physical and emotional health, interpersonal relationships, and daily activities, thus negatively impacting a patient’s quality of life. It can also cause economic hardships including increased hospital stays.

There are barriers leading to the undertreatment of BTCP, a common one being fear of opioid abuse, addiction, misuse, and/or diversion. Other barriers include concerns about adverse effects, perceived low priority of pain therapy, and shortcomings in medical training in this area of pain management.9

BTCP can occur spontaneously with no known triggers or patterns (idiopathic); be triggered by voluntary or involuntary actions (incidental); or be triggered by diagnostic or therapeutic procedures (procedural). Other types of BTCP include effects of cancer on anatomical structures, chemotherapy-related toxicity, nociceptive pain, neuropathic pain, and mixed pain. This pain is severe, is of short duration, and has a rapid and unpredictable onset. It is complex and varies significantly between patients. As a result, pharmacologic treatment should be individualized based on clinical presentation, etiology, and pathophysiology.9

Pharmacologic treatment for BTCP is aimed at having a rapid onset (~10 minutes), short duration of action (≤2 hours), tolerable adverse-effect profile, and efficacy for severe pain. Fast-acting opioids, such as transmucosal fentanyl, have replaced short-acting opioids (i.e., oral morphine and oxymorphone) as first-line therapy. The onset of action of these first-line agents ranges from 3 to 5 minutes, and the duration of action ranges from 1 to 2 hours. Depending on the formulation, transmucosal fentanyl can provide better relief than IR morphine or oxycodone, minimize first-pass metabolism, and allow for rapid drug absorption.10

Second-line therapy includes nonopioid analgesics such as acetaminophen, NSAIDs, and intranasal ketamine. Midazolam may be beneficial for incidental, movement-related BTCP, and nitrous oxide may be beneficial for incidental BTCP in terminally ill patients.10

Adjuvant analgesics can be used in combination with opioids. Anticonvulsants (e.g., gabapentin, topiramate, pregabalin) are first-line in patients with refractory neuropathic pain without comorbid depression, and antidepressants (e.g., duloxetine) are first-line for those with comorbid depression. Anticholinergics, such as oxybutynin and scopolamine, are used as an adjunctive treatment for visceral nociceptive pain. Psychostimulants, including methylphenidate and modafinil, are used for opioid dose escalation when opioid-related adverse events (especially sedation) are of concern.10

Selecting a route of administration to provide adequate analgesia is important. The preferred and least invasive route is oral. If rapid onset is required, then continuous infusion, IV, SC, or IM routes should be used. The onset of action of an IV route is 15 minutes at peak versus 60 minutes at peak for the oral route and about 30 minutes at peak for the SC route. All patients should receive follow-up treatment so that pain can be monitored continually. For most cancer patients, pain relief should be continuous (around-the-clock dosing), along with something for BTCP. If the patient comes back and the pain is inadequately controlled, titration of the current dose is recommended, as well as an opioid rotation.1

Conclusion

Pain management for cancer patients is a growing discipline that requires pharmacists to stay up-to-date on guidelines in order to make proper recommendations. It is difficult to manage pain for an oncology patient, as many other factors play a role and require special attention. All pain medications that the patient is taking must be reviewed for drug-drug interactions. In addition, other disease states and the age of the patient must be considered when selecting pain medication, especially when the patient is on chemotherapy.

REFERENCES

1. Adult cancer pain. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Version 2.2013. Fort Washington, PA: NCCN; 2013:MS1-MS20.
2. Cohen MZ, Easley MK, Ellis C, et al. Cancer pain management and the JCAHO’s pain standards: an institutional challenge. J Pain Symptom Manage. 2003;25:519-527.
3. Baumann T, Strickland J, Herndon C. Chapter 69. Pain management. In: DiPiro JT, Talbert RL, Yee GC, et al, eds Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York, NY: McGraw-Hill; 2011. http://accesspharmacy.mhmedical.com/content.aspx?bookid=462&Sectionid=41100843. Accessed January 18, 2014.
4. Wong-Baker FACES Pain Rating Scale. www.wongbakerfaces.org. Accessed February 14, 2014.
5. WHO’s cancer pain ladder for adults. World Health Organization. www.who.int/cancer/palliative/painladder/en/. Accessed February 14, 2014.
6. Ripamonti CI, Bandieri E, Roila F; ESMO Guidelines Working Group. Management of cancer pain: ESMO Clinical Practice Guidelines. Ann Oncol. 2011;22(suppl 6):vi69-vi77.
7. Zohydro ER (hydrocodone bitartrate extended release capsules) package insert. Gainesville, GA: Alkermes Gainesville LLC; 2013.
8. Young CA. Controversy surrounds FDA approval of Zohydro. American Pharmacists Association. www.pharmacist.com/controversy-surrounds-fda-approval-zohydro. December 1, 2013. Accessed January 18, 2014.
9. Margaret C, Julia J, Lopez R, et al. Breakthrough cancer pain—still a challenge. J Pain Res. 2012;5:559-566.
10. Escobar Y, Manas A, Julia J, et al. Optimal management of breakthrough cancer pain (BCP). Clin Transl Oncol. 2013;15:526-534.

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