Breaking Through Breakthrough Cancer Pain

OCTOBER 19, 2017
Jerry Barbee Jr., PharmD, BCPS, CPh; Carmen Russell, PharmD, BCPS; Joe Cotton, 2018 PharmD Candidate; and Jessica Fleischfresser, 2018 PharmD Candidate
The International Association for the Study of Pain describes pain as “an unpleasant sensory and emotional experience arising from actual or potential tissue damage or described in terms of such damage.”1

Between 20% and 50% of cancer patients experience chronic pain. These patients often suffer from intense pain spikes that break through the control of chronic pain medications. Breakthrough pain (BTP) estimates vary, but as many as 50% of patients diagnosed with cancer and chronic pain have pain levels that are not adequately controlled.2 BTP, specifically breakthrough cancer pain (BTcP), creates multiple burdens on patients and the health care system. The Guidelines for the Management of Breakthrough Pain in Patients with Cancer defines BTcP as a temporary exacerbation of pain that arises, despite the use of around-the-clock opioids for pain management.3 Without proper management, uncontrolled pain increases prescriber visits, hospital admissions, and the duration of in-hospital stays, thus increasing medical expenses and health care facility expenditures.3 The Medical Expenditure Panel Survey found total pain-related costs ranging from $560 billion to $635 billion annually. The total health care costs of this economic burden ranges from $261 billion to $300 billion each year, with $299 billion to $334 billion in lost productivity.4 Additionally, patients can have comorbid conditions that may be caused or exacerbated by pain. In many studies, pain has been linked to mental disorders such as depression, anxiety, and chronic illnesses.5 By focusing on care that improves patient quality of life (QOL), a clinician can reduce comorbid conditions, improve patient survival, and decrease the significant costs of care.6

The first step in understanding BTP is having a comprehensive knowledge of the various categories of pain. Etiology of pain can be neurological, nociceptive, or mixed in nature. Pain involving the nerves is referred to as neurological pain. Nociceptive pain is classified into 2 groups: somatic, involving bones and muscles; or visceral, involving body organs. Cancer patients often experience a mixed type of pain, which occurs from the combination of neurological and nociceptive pain.7

Episodes of BTP can occur, despite adjusting chronic pain medications and may present as a burning, aching, or searing sensation. BTP originates from various sources. When pain originates from an unknown cause, it is referred to as “spontaneous,” whereas pain occurring from an identifiable trigger is referred to as “incident” pain.

Incident pain is provoked by known causes and can be further classified as either volitional, pain provoked by voluntary movement, such as walking, or nonvolitional pain, caused by factors outside an individual’s control, such as bowel distension.7 

Cancer patients often experience incident pain from the cancer but may also experience spontaneous pain. At the end of a scheduled dosing interval, patients can experience a decreased analgesic effect caused by elimination of their chronic pain medication, which can be mistaken as BTcP. This is not a true exacerbation of BTcP, but rather, an “end-of-dose failure.” BTP peaks around 3 minutes, lasts from 30 to 60 minutes and is an intense level of pain. The recommended treatment consists of rapid- or short-acting opioid analgesics that can safely and effectively mitigate a patient’s pain.3

Pain associated with cancer may not originate within the cancer itself. When cancer invades surrounding nerves, bones, or organs, it causes pain. As cancer metastasizes, pain is more likely to occur. About 80% of advanced-cancer patients experience moderate to severe pain.8 In a study of 100 patients (95 with cancer), BTcP occurred in 75%, 30% were categorized as incidental, and 26% as spontaneous.9 The results of another study conducted on 2266 cancer patients found that 85% experienced pain caused by cancer, 17% by antineoplastic treatment, and 9% unrelated to cancer.10

The Cancer Pain Relief Programme of the World Health Organization (WHO) created a 3-step “analgesic ladder” to empirically assess and treat cancer-associated pain, with a claim of 70% to 90% effectiveness.11 The ladder was released in 1986 and has not been updated since initial implementation. The need for an updated ladder (Figure 1) has been proposed with the addition of new opioids, allowance to move in a bidirectional fashion, and a fourth step that addresses treatment crisis of chronic pain with interventional treatments.11 On this updated ladder, severe cancer pain should be advanced to step 3 and treated with strong opioid analgesics to avoid the affliction of inadequate pain relief.12 First-line options, such as nonopioids and adjuvant analgesics, do not possess the same attributes as opioid analgesics and may have limited application and utility.13 Regardless of which edition is used, the WHO analgesic ladder is based on core principles for ideal management of chronic pain that are still applicable. However, it does not specifically define a stepwise strategy for BTcP. In summary, analgesics should be administered orally at regularly scheduled intervals. Patients should be provided detailed personal instructions with a dose that adapts to address their individual pain level.


Without proper clinical recognition and intervention, BTP diminishes QOL. Uncontrolled BTP is directly correlated with increased despondency, loss of interest in activities and relationships, and poor medical outcomes.15 Health care providers play a crucial role in coordinating BTP management strategies by using subjective data and clinical tools. A thorough patient interview is necessary to establish a clear understanding of baseline pain and differentiating it from BTP. Experts recommend a formulated protocol, such as an algorithm (Figure 2), to diagnose BTP and improve patient care.3 Techniques, such as the PQRSTU assessment (precipitating, palliating, previous treatment, quality, region/radiation, severity, temporal, you[U] effect on the patient), aid the process of understanding the characteristics of pain episodes.16


Patients with cancer pain need a combination of pharmacological and nonpharmacological strategies to achieve “balanced analgesia.”18,19 Nonpharmacological therapies are beneficial and empower patient autonomy. Examples such as lifestyle modifications and cognitive behavioral therapy are valuable alone or as adjunct to pharmacological therapy. Modifying daily routines, redistributing labor intensive activities, and allowing others to assist the patient can minimize breakthrough episodes. Medical devices, ie, braces, heating pads, and transcutaneous electrical nerve stimulation units may assist in reducing pain.2,18 Patients who suffer from incident pain, such as physical therapy, should use pharmacological therapies 30 to 60 minutes before sessions to minimize pain and increase activity.19

When selecting a breakthrough medication regimen, factors to consider are cost effectiveness, adverse effects, onset of action, duration, and patient tolerability.2 Oral opioids are the backbone of many 24-hour treatment regimens, and the immediate-release forms may also be used for breakthrough pain. Customarily, a rescue dose for BTP is calculated by taking 10% to 20% of a patient’s total daily morphine milligram equivalent (MME) (Table 1) and providing this dose, as needed. Although this is a safe initial dose-finding strategy, evidence has shown that using a set percentage of the total daily dose is inadequate for controlling about two-thirds of BTcP. These findings further demonstrate that optimal dosing should be individualized and titrated to patient needs.21

Although oral opioids are useful for incidental pain, their use is limited when treating BTcP that occurs spontaneously due to their slow onset of action that can take up to 30 minutes (Table 2). BTcP episodes would have already lapsed by the time the opioid has taken effect. Rapid onset opioids (ROOs) are ideal for mimicking spontaneous BTcP because their effect occurs within minutes.21 Fentanyl is the only ROO approved for BTcP in the United States. Several formulations are available, all of which deliver analgesia within 5 to 15 minutes. Fentanyl is a synthetic μ-opioid receptor agonist that is about 80 times more potent than morphine.22,23 Its potency, route of administration, and lipophilic nature allow a rapid onset without invasive methods.24 Fentanyl should be reserved for opioid-tolerant patients receiving at least 60 MME per day or an equivalent opioid for 7 days (Table 3). With no approved conversion strategy to fentanyl, practitioners must use the manufacturer’s approved titration schedule (Table 4). Before therapeutic adjustments are made, patient specific factors such as age, opioid tolerance, and adverse drug reactions (ADRs) should be considered.

Establishing an open dialogue is essential for preventing ADRs and finding a therapeutic window appropriate to alleviate BTcP. Signs of opioid toxicity include over-sedation, respiratory depression, and pinpoint pupils. In general, the elderly population and patients with renal dysfunction are more susceptible to opioid toxicities and require more frequent monitoring. Emergency reversal agents, such as naloxone, should always be included in treatment regimens that use ≥50 MME per day. Patients and caretakers should be counseled on appropriate naloxone use and administration in the case of suspected opioid overdose. Inadequately controlled pain can lead to medication overuse in an effort to gain relief, putting patients at risk for toxicity and ADRs.25

The complexity of breakthrough pain can be an all-consuming issue for patients. As health care providers, we must individualize pain management and liberate patients through education. Clinicians should maintain an open line of communication with the patient when establishing this precarious balance between unfavorable effects and pain control. Even with careful selection, adverse effects may develop when managing breakthrough pain. The clinician must seek to optimize care for the patient by effective use of treatment algorithms, recognition of diminished chronic pain management control, and targeting pharmacological and nonpharmacological therapy interventions. With proper management of pain medications and the use of treatment algorithms for BTcP, clinicians can work with patients, allowing them to have the best quality of life.




Jerry Barbee Jr., PharmD, BCPS, CPh, and Carmen Russell, PharmD, BCPS, are clinical pharmacists at HCA West Florida Hospital.

Joe Cotton is a 2018 PharmD Candidate at Auburn University.

Jessica Fleischfresser is a 2018 PharmD Candidate at Florida Agricultural and Mechanical University.


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