Breakthrough Pain: The Final Frontier

Pharmacy Times, August 2014 Pain Awareness, Volume 80, Issue 8

Each patient's breakthrough pain has a unique mix of clinical features, just as each patient's clinical experience of chronic pain differs.

Each patient’s breakthrough pain has a unique mix of clinical features, just as each patient’s clinical experience of chronic pain differs.

The health care profession has made tremendous strides in pain management in the past 20 years. Patients today are more likely to receive counseling, have access to physical therapy, and be prescribed analgesics when they have chronic pain. However, 1 type of pain remains seriously undertreated: breakthrough pain (BTP). Between 64% and 90% of cancer patients experience intermittent flares of pain,1 as do a majority of patients with chronic nonmalignant pain.2 This article explores BTP, with an emphasis on ways to treat it successfully.

Pain occurs in many forms. To have BTP, patients must, by definition, have background pain—chronic pain that occurs fairly constantly and predictably for more than 12 hours a day for at least a week. BTP is a transient pain exacerbation lasting 30 minutes or less that occurs despite relatively stable and adequately controlled background pain. BTP tends to occur more often during the day. Table 13-5 describes 3 types of BTP. In general, BTP is acute in onset, short in duration, and moderate to severe in intensity. Each patient’s BTP has a unique mix of clinical features, just as each patient’s clinical experience of chronic pain differs.3

Putting the Brakes on BTP

Before creating a BTP management plan, clinicians should use the PQRSTU (precipitating, palliating, previous treatment, quality, region/radiation, severity, temporal, you [U] effect on the patient) assessment technique.6 Once the patient’s pain is clearly profiled, several effective strategies can manage BTP. Some of them are obvious (eg, identify and treat the underlying cause, avoid precipitating factors, use nonpharmacologic methods and interventions). Other strategies require attention to the patient’s medication regimen. Clinicians may need to modify the around-the-clock background analgesic regimen, and if the BTP continues, prescribe rescue medication as needed.3

Ideal pain rescue agents work quickly and have short durations of action. That is, they must mirror a BTP episode’s temporal characteristics. Nonopioid and adjuvant analgesics usually lack these characteristics, and even immediate-release opioids act too slowly to provide ideal relief because they require 20 to 30 minutes to take effect, may have a duration of effect of 3 to 6 hours, and exacerbate side effects. The drug should have an analgesic potency sufficient to relieve severe pain.3,7 Fortunately, a number of options are available to provide relief.

Transmucosal Opioids

Transmucosal opioid products include intranasal and oral fentanyl formulations, also called rapid-onset opioids (ROOs). A recent metaanalysis found that intranasal fentanyl products (Instanyl, PecFent) and oral transmucosal fentanyl products (Effentora, Actiq, Abstral, Onsolis) yield lower pain intensity scores and higher pain relief scores than placebo and morphine at all time points. Oral immediate-release morphine took effect 45 minutes after administration.8,9 The new oral transmucosal/sublingual fentanyl (Subsys) was not included, as it had not been approved when the study was conducted.

ROOs should only be administered to opioid-tolerant patients receiving oral morphine equivalents of at least 60 mg. Different fentanyl formulations vary in pharmacokinetic properties and ease of use. All of these systems theoretically deliver analgesia within 5 to 15 minutes.10 With oral opioids, rescue doses are calculated as a percentage of the maintenance dose. Clinicians should titrate patients’ transmucosal opioid doses, however, using each product’s complete prescribing information as a guide because the dose of opioid background medication and the optimal dose of transmucosal opioid formulations (the dose that is most effective with an acceptable side effect profile) correlate poorly, so the rescue dose is unpredictable.11

Some clinicians continue to use immediate- release opioid formulations to preempt predictable BTP episodes. In these situations, patients are dosed 20 to 30 minutes before the anticipated trigger, whether it is movement, physical manipulation, or a procedure.12 The usual starting dose is 1/10 to 1/6 of a patient’s total daily opioid dose.13

Some patients find adequate relief from nonopioid analgesics such as acetaminophen and nonsteroidal antiinflammatory drugs. Few studies have investigated nonopioid drugs.14

Treatment Challenges

Because the incidence of cancer and noncancer pain increases with age, BTP is a concern in elderly patients. Elders’ loss of therapeutic reserve, elders’ comorbidities, and geriatric syndromes complicate pharmacotherapy. In addition, altered cognition and elders’ beliefs about pain and medication (see below) are challenges.13,15 Elders who have BTP are often undertreated. 16 Online Table 213,15,16 describes concerns about BTP in this population.

Table 2: Breakthrough Pain: Unique Concerns in the Elderly

  • Elders generally respond to lower opioid doses (30% to 50% lower than those needed in younger adults), but every elder deserves careful drug titration based on individual response.
  • Elders are more susceptible to opioid toxicity.
  • When adverse effects limit dose escalation, switching to an alternative opioid or formulation may help.
  • Clinicians should assess older patients’ pain continuously—before and after analgesic treatment.
  • Cognitively impaired elders may not remember to ask for as-needed analgesics.
  • It is imperative to optimize around-the-clock dosing for background pain.
  • Clinicians and caretakers should watch for signs of pain (eg, wincing, guarding behaviors, vocalizations)Adapted from references 13, 15, and 16.

Appropriate adherence to analgesic medication is also a challenge. One study found that only 33% of patients used rescue medication consistently for BTP. Approximately 37% said the pain was not always severe enough, 23% said they worried about tolerance, 17% preferred to endure the pain, 12% worried about addiction, 10% said prescribed medication didn’t work, and 8% said the prescribed medication worked too slowly. Just 7% cited side effects as a barrier.17 These finding are similar to clinical observations. Patients often fear overmedication. Pharmacists can help by counseling patients about the correct way to use opioids for BTP and by encouraging patients to use them for every episode of BTP.


Improved pharmacotherapy has helped many patients live longer with chronic disease. Chronic pain often accompanies longer life, and adequate pain management can help patients function better and generally enjoy an improved quality of life. Lifestyle changes such as being aware of physical limitations, pacing oneself, avoiding activities that precipitate pain, and using ice/heat packs, massage, exercise, repositioning, or immobilization therapy can help. In addition, pharmacists should encourage patients to avoid catastrophic thinking and to take analgesics when they need them.

Virginia Bartok is a pharmacist whose primary practice was in indigent care, and she currently provides case management for several geriatric patients.


1. Caraceni A, Martini C, Zecca E, et al. Breakthrough pain characteristics and syndromes in patients with cancer pain: an international survey. Palliat Med. 2004;18:177-183.

2. Study in multidisciplinary pain research. Acute and chronic pain: where we are and where we have to go; from bench to bedside. 5th annual meeting, March 2013. Minerv Anesthes. 2013;79(suppl 1):1-83.

3. Davies AN, Dickman A, Reid C, Stevens AM, Zeppetella G. The management of cancer-related breakthrough pain: recommendations of a task group of the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland. Eur J Pain. 2009;13:331-338.

4. Portenoy RK. Treatment of temporal variations in chronic cancer pain. Semin Oncol. 1997;5:7-12.

5. Mercadante S, Zagonel V, Breda E, et al. Breakthrough pain in oncology: a longitudinal study. J Pain Symptom Manag. 2010;40:183-190.

6. PQRST method for pain assessment. Critical Care Nursing website. Accessed June 10, 2014.

7. Müller-Schwefe G, Ahlbeck K, Aldington D, et al. Pain in the cancer patient: different pain characteristics CHANGE pharmacological treatment requirements. Curr Med Res Opin. 2014; Jun 10:1-14.

8. Zeppetella G, Ribeiro MD. Opioids for the management of breakthrough (episodic) pain in cancer patients. Cochrane Database Syst Rev. 2006;1:CD004311.

9. Zeppetella G, Davies A, Rios C, Eijgelshoven I, Jansen JP. A network meta-analysis of the efficacy of opioid analgesics for the management of breakthrough cancer pain episodes. J

Pain Symptom Manag. 2014;47:772-785.

10. Mercadante S. Pharmacotherapy for breakthrough cancer pain. Drugs. 2012;72:181-190.

11. Davies AN. Breakthrough cancer pain. Curr Pain Headache Rep. 2014;18:420.

12. Caraceni A, Hanks G, Kaasa S, et al; the European Association for Palliative Care (EAPC). Use of opioid analgesics in the treatment of cancer pain: evidence-based recommendations from the EAPC. Lancet Oncol. 2012;13:e58-e68.

13. Davis MP, Srivastava M. Demographics, assessment and management of pain in the elderly. Drugs Aging. 2003;20:23-57.

14. Gannon C, Davies A. Non-opioid drugs. In: Davies A, ed. Cancer-Related Breakthrough Pain. Oxford, UK: Oxford University Press; 2006:83-96.

15. Pautex S, Vogt-Ferrier N, Zulian GB. Breakthrough pain in elderly patients with cancer: treatment options. Drugs Aging. 2014;31:405-411.

16. Mercadante S, Arcuri E. Pharmacological management of cancer pain in the elderly. Drugs Aging. 2007;24:761-776.

17. Bedard G, Hawley P, Zhang L, et al. A survey of Canadian cancer patients’ perspectives on the characteristics and treatment of breakthrough pain. Support Care Cancer. 2013;21:2557-2563.