Breakthrough Cancer Pain

Pain is a frequent symptom among patients with cancer. Most patients with malignant cancer experience recurrent episodes of acute pain, while chronic pain severe enough to warrant opioid therapy is present in 30% to 50% of patients undergoing antineoplastic therapy and 75% to 90% of patients with advanced cancer.^1,2 Also, among the 14 million cancer survivors in the United States, an estimated 40% still experience some type of pain.³

Both acute and chronic pain can have many different origins. Acute pain often accompanies invasive surgeries or therapeutic or treatment complications, or it can be related to the malignancy itself. The etiology of chronic pain can be quite diverse, and the frequency and severity can vary with the type of neoplasm, stage and extent of disease, prior treatment, comorbidities, and other factors. Tissue injury from the neoplasm is the primary etiology in 75% of patients with chronic cancer pain, and the remainder experience pain related to the lasting effects of antineoplastic therapy or comorbidities.

Because of the high prevalence of cancer pain, all patients should be assessed and routinely screened. Undertreatment and uncontrolled pain can result in unnecessary suffering, a decreased ability to cope with illness, interference with daily activities, and repeat and extended hospital admissions. Patients with uncontrolled pain experience more anxiety and depression, can have delays or disruptions in anticancer treatment, and have a higher cost of treatment.^4,7 When available treatment guidelines for patients with cancer are followed, 70% to 90% can achieve adequate pain relief.

EPIDEMIOLOGY

Breakthrough pain has been defined as a transient exacerbation of pain that occurs against a background of chronic pain otherwise controlled by a scheduled opioid regimen.^5,6 Of the patients with cancer experiencing chronic pain, one-half to two-thirds report episodic breakthrough pain. Some studies report this number is as high as 90% in patients with advanced cancer.

On average, breakthrough pain episodes are characterized as rapid in onset and being of moderate to severe intensity. These episodes can come on in seconds, with the average duration lasting 3 to 30 minutes and occurring 1 to 4 times a day. However, each patient is different, so proper assessment is needed to individualize treatment.

TREATMENT ​​​​​​​

Breakthrough pain is usually managed pharmaceutically, with supplemental doses of opioids or rescue medication.⁶

Short-acting opioid formulations, such as immediate-release morphine, oxycodone, hydrocodone, and oxymorphone, are usually first-line treatment for moderate to severe breakthrough of pain, with the rescue dose being calculated as 10% to 20% of the s basal daily requirement of the opioid, with the option to repeat the rescue dose hourly as needed.^5,6,8 Immediate-release opioids have an onset of action between 10 and 30 minutes, with the peak analgesic effect occurring at 1 to 1.5 hours. A disadvantage of immediate-release opioids is that sometimes the pain has ceased by the time the analgesic effect takes over, exposing the patient to unnecessary medicine and adverse effects (AEs). The oral route also may not be feasible for patients with mucositis, dysphagia, or severe nausea.

A rapid-onset transmucosal fentanyl product may be a better alternative for some patients, as it works quickly and has specific indications for breakthrough cancer pain.^5,6,8 Available formulations include an oral transmucosal tablet formulation (Actiq), an effervescent fentanyl buccal tablet (Fentora), an immediate-release transmucosal tablet (Abstral), a nasal spray (Lazanda), and a sublingual spray (Subsys). Recommended starting doses of transmucosal fentanyl are either the lowest or next-to-lowest available dose, as trials have not confirmed a dose proportionate to the baseline dose. The onset of analgesia ranges between 5 and 15 minutes, with a peak analgesic effect between 1 and 2 hours.^6,8 However, the cost of transmucosal fentanyl preparations can be a barrier to some.

Few studies have directly compared the transmucosal fentanyl formulations with one another, but studies have confirmed the efficacy and rapid onset of action of these medications.⁶ All transmucosal fentanyl products and other select opioids have a mandatory risk evaluation and mitigation strategy, aimed at reducing risk, addiction, misuse, abuse, and unintentional overdose.

Immediate-release oral opioids are appropriate to treat pre- dictable episodes of pain when administered at least 20 minutes before the potential pain trigger. End-of-dose failure and uncontrolled persistent pain are usually managed by evaluating and adjusting the scheduled opioid regimen.⁶ Nasal, subcutaneous, or intravenous opioids may also be used, as well as combination products, depending on the needs and condition of the patient.

ADJUVANT ANALGESICS, INTERVENTIONAL THERAPIES

Adjuvant analgesics, or co-analgesics, may be added to enhance analgesia or treat AEs in patients with chronic pain.⁹ Nonopioid analgesics, such as acetaminophen and nonsteroidal anti-inflammatory drugs, work well for some patients. They are generally used to treat milder pain and to help reduce the number of narcotics being taken.

Other options when managing chronic cancer pain include glucocorticoids, analgesic antidepressants, alpha-2 adrenergic agonists, cannabinoids, and some topical therapies.⁹ As a rule, adjuvant analgesics should be considered only after efforts have been made to optimize opioid therapy. This approach ensures that the second drug is needed, reduces the risk of additive toxicity, and limits confusion when determining the source of an AE.

Patients unable to achieve adequate analgesia or who experience intolerable AEs may be candidates for interventional therapies, such as nerve blocks, vertebroplasty, kyphoplasty, and epidural/intrathecal infusions.¹⁰

OPIOID ADVERSE EFFECTS

Some of the most common and dose-limiting AEs of opioids are nausea and vomiting, constipation, mood changes, delirium, pruritus, respiratory depression, and somnolence. Tolerance does develop to some AEs, although not with constipation, which should be anticipated and treated prophylactically.

Because opioids are potentially abusable drugs and many patients fear dependence or tolerance, monitoring for abuse or misuse should be part of routine pain assessment.

PHARMACIST’S ROLE

Along with advising on agent selection and dosing, management of AEs, and practitioner education, pharmacists can play a big role in patient education. According to a survey done on cancer pain, about 23% of patients said they were worried about medication tolerance, 12% were worried about addiction, 10% said the medication didn’t work, 8% said the medication worked too slowly, and 7% feared AEs. A pharmacist can offer counseling on all these points and present recommendations for a therapy adjustment or switch.

CONCLUSION ​​​​​​​

Breakthrough pain is prevalent among patients with cancer and, if left untreated, can have major consequences on a patient’s therapy, quality of life, and survival. Successful care includes proper assessment; treatment of the underlying cause, if possible; and selection of an agent that will optimize analgesia and minimize AEs. Breakthrough pain is most commonly treated with opioids because of their tolerability, multiple routes of administration, and effectiveness for all pain types.

Joanna Lewis, PharmD, MBA, graduated from the Medical University of South Carolina in 2007. Since then, she has held a variety of pharmacy practice roles, most recently a leadership position in the Department of Pharmacy at Duke University Hospital. Some of her responsibilities included medication safety, quality improvement, oversight of the nancial charge capture process, and coordination of the implementation of a new technology system. She is passionate about acting as a precept and mentoring new practitioners, as well as making the practice of pharmacy better.

References

1.van den Beuken-van Everdingen MH, de Rijke JM, Kessels AG, Schouten HC, van Kleef M, Patijn J. Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol. 2007;18(9):1437-1449.

2. van den Beuken-van Everdingen MH, Hochstenbach LM, Joosten EA, Tjan-Heijnen VC, Janssen DJ. Update on prevalence of pain in patients with cancer: systematic review and meta-analysis. J Pain Symptom Manage. 2016;51(6):1070-1090.e9. doi: 10.1016/j.jpainsymman.2015.12.340.

3. Paice J, Portenoy R, Lacchetti C, et al. Management of chronic pain in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2016;34(27): 3325-45. doi: 10.1200/JCO.2016.68.5206.

4. Portenoy RK, Bruns D, Shoemaker B, Shoemaker SA. Breakthrough pain in community-dwelling patients with cancer pain and noncancer pain, part 1: prevalance and characteristics. J Opioid Manag. 2010;6(2):97-108.

5. Coluzzi PH, Schwartzberg L, Conroy JD, et al. Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Pain. 2001;91(1-2):123-130.

6. National Comprehensive Cancer Network. Adult cancer pain (version 2.2016). The Oral Cancer Foundation website. oralcancerfoundation.org/wp-content/uploads/2016/09/pain.pdf. Accessed July 5, 2017.

7. Webster LR. Breakthrough pain in the management of chronic persistent pain syndromes. Am J Manag Care. 2008;14(5 suppl 1):S116-S122.

8. Winiarczyk K, Kneti-Wroblewska M. Breakthrough pain in cancer patients. Oncol Clin Practice. 2016;12(1):1-6.

9. Portenoy RK, Ahmed E, Keilson YY. Cancer pain management: adjuvant analgesics (coanalgesics). UpToDate website. uptodate.com/contents/cancer-pain-management-adjuvant-analgesics-coanalgesics. Updated March 6, 2017. Accessed June 28, 2017.

10. Portenoy RK, Copenhaver DJ. Cancer pain management: interventional therapies. UpToDate website. uptodate.com/contents/cancer-pain-management-interventional-therapies. Updated May 8, 2017. Accessed June 28, 2017.