New Thinking in Breakthrough Pain

As if chronic pain by itself isn’t enough to manage, breakthrough pain adds another layer of agony for many patients. An intense transient flare of pain against a background of well-controlled chronic pain, breakthrough pain is excruciating, unpredictable, and debilitating. Given its urgent nature, patients suffering from breakthrough pain don’t just visit the doctor’s office more often; they also head to emergency rooms and require more hospitalizations. Not only is breakthrough pain expensive, it’s emotionally (and physically) draining for patients who have to deal with its terrible unpredictability. In a survey of 1,000 patients with cancer pain, those who had breakthrough pain made about four office visits per year related to the breakthrough pain; on average, they also made at least one visit to the ER, and were hospitalized at least once because of the pain. Not surprisingly, breakthrough pain increases the cost of cancer care; cancer patients with breakthrough pain spend on average $12,000 annually on pain-related hospitalizations, emergency visits, and physician office visits, five times more than the average cost of $2,400 for cancer patients without breakthrough pain. Breakthrough pain was first reported in cancer patients with metastatic disease and chronic pain in the 1970s. It’s traditionally been treated with morphine, but now, three FDA-approved rapid-acting fentanyl products are available in the United States to treat breakthrough pain in cancer patients. The new products have ushered in some new thinking about the best way to treat this unpredictable pain.

Breakthrough pain in low back pain and neuropathy

According to a 2006 Journal of Pain article that surveyed patients in nine pain programs, 74% of patients with (non-cancer) chronic pain who had controlled baseline pain also had breakthrough pain. Half of those surveyed were low-back pain patients, reports study author Russell Portenoy, MD, Chairman of the Department of Pain Medicine and Palliative Care at Beth Israel Medical Center in New York City. Back pain patients experienced a median of two breakthrough pain episodes daily, with half of the patients reporting their pain reached the “severe” or “excruciating” level within 10 minutes. Each episode lasted a median of 55 minutes, according to Daniel Bennett, MD, founder of Integrative Treatment Centers in Denver, Colorado, who published a back-pain-specific substudy of Portenoy’s original study. Three-fourths of back pain patients identified a precipitant for the breakthrough pain, nearly always activity-related. However, the onset of a breakthrough pain episode was unpredictable half the time and consistently predicted in just 13% of cases. Patients used medication, rest, heat, moving, stretching, and physical therapy to reduce their breakthrough pain intensity; however, these interventions succeeded in just 27% of breakthrough pain instances.

The breakthrough pain picture is similar in patients with neuropathies. In the aforementioned survey, neuropathic pain patients experienced a median of two episodes of breakthrough pain a day lasting a median 60 minutes each. Nondiabetic neuropathy and complex regional pain syndrome were the most common diagnoses in patients with breakthrough pain. Patients defined a precipitant for their breakthrough pain episodes 62% of the time, but were able to consistently predict the episodes just 52% of the time. They used techniques similar to those tried by back pain patients to manage their breakthrough pain; however, the interventions were consistently effective in just 28% of incidents.

In patients with chronic low back pain or neuropathic pain who are functioning poorly, breakthrough pain is a possible contributor. “When what has worked previously is no longer working, I re-evaluate the pain pathology and topography and start thinking about breakthrough pain,” says Bennett. There are three primary reasons that Bennett says can cause pain levels to drastically increase in stable patients: Failure of the primary pain medication; prescribing the wrong medication for the patient’s type of pain; or genuine breakthrough pain. Because neuropathic pain typically results from underlying nerve damage, says Bennett, identifying the right treatment results in long-term management and stability because the underlying pathology does not shift. However, in patients with low-back pain, the pathology needs be reinvestigated, because of new damage due to the constant physical stress on the back. New pathology may be present that is causing a breakthrough pain. “Low-back pain patients have some similarities to patients with active cancer,” Bennett says. “In both cases we’re dealing with evolving physical systems.”

Asking the right questions Breakthrough pain is a clinical diagnosis that requires a structured interview to properly evaluate it within the context of overall chronic pain. “Breakthrough pain has such variability and multiple factors, including mechanisms of pain, the amount and type of medication, degree of anxiety, and emotional status, that it is hard to come up with a standardized tool for assessing it,” says Lynn Webster, MD, Medical Director of Lifetree Clinical Research and Pain Clinic in Salt Lake City. For example, one literature review identified more than 20 pain scales and questionnaires published between 1983 and 2000, including a 1999 paper by Portenoy, et al. that used the “Breakthrough Pain Questionnaire." The Breakthrough Pain Questionnaire, notes Portenoy, is a five-minute, structured interview that is designed to characterize breakthrough pain and provides a good assessment.

Clinicians should assess whether the patient has pain most of the time (baseline chronic pain) and whether that baseline pain is controlled to a moderate or lower level at all times. In a patient with controlled baseline pain, clinicians should determine whether the patient has temporary flares of severe or excruciating intensity. If this is the case, the clinician should consider a diagnosis of breakthrough pain and ascertain how often the flares occur, the precipitating factor (if any), and the patient’s response to the flare.

Bennett instructs his patients to keep pain diaries and at each appointment has them complete the Brief Battery for Health Improvement (BBHI) test, which assesses pain and function, depression, and anxiety. In one stable back pain patient seen for a routine follow-up appointment, the BBHI showed he had severe pain, high levels of depression and anxiety, and was contemplating suicide, says Bennett. “Sitting in my exam room, he was as calm as always. This patient turned out to be under significant interpersonal stress including marriage separation, job loss, and pending loss of his benefits. His pain was clearly psychological in origin.”

Both Bennett and Webster agree that physicians should evaluate and treat a patient’s depression and anxiety before treating his or her breakthrough pain. “Anxiety and emotional status often set different thresholds for breakthrough pain in patients,” says Webster. “We know anxiety will influence the overall amount of a pain patient’s experience, and will also increase susceptibility to episodic pain.” Behavioral and psychological strategies such as cognitive behavioral therapy (CBT) should be the first-line treatment. “Treating anxiety doesn’t always have to be with pharmacology,” Webster notes. For instance, Bennett referred the previously described low-back pain patient to psychotherapy to help him cope. As the patient’s mental status improved, so did his pain.

Rapid relief

Identification of breakthrough pain in low-back pain and neuropathies has led to clinical trials of some fentanyl preparation in these populations. Studies of 77 low-back pain patients and 79 patients with neuropathic pain found that the rapid-acting formulation of fentanyl buccal tablets effectively relieved breakthrough pain. In the back pain study, fentanyl buccal tables reduced breakthrough pain intensity by at least one third of peak levels for 65% of patients compared with only 28% of patients receiving placebo. In the neuropathic pain study, 66% of patients experienced similar results. “Strong rapid-onset medications are warranted in individuals with severe episodic pain,” says Webster. However, “they need to be used carefully, particularly in patients with significant comorbid conditions. The magnitude of pain needs to warrant the strength of the medication.”

There are a variety of other pharmacologic and nonpharmacologic strategies that can be used in patients whose breakthrough pain is not intense enough to warrant treatment with rapid-acting opioids. For incident pain, short-acting opioids and heat or ice are effective. For spontaneous pain, CBT and breathing techniques can also be used. Although concerns exist about the potential for abuse with rapid-acting opioids, Bennett notes that abuse is a psychological pathology. “People who are abusers are going to abuse anything you give them.” Universal precautions and appropriate risk mitigation is about understanding with whom the pathology lies and treating it appropriately. That means clinicians must:

• Understand the patient, his or her job, background, and psychology. “I wouldn’t give (pregabalin) to someone who operates large machinery (because of the dizziness) and, likewise, I wouldn’t give opioid therapy to a young man with bipolar disorder,” says Bennett.

• Monitor the patient to assess clinical issues, pain, and overall function. “We need to be just as diligent in monitoring our (pain) patients as we would if we’re giving insulin to people with diabetes,” Bennett says.

• Conduct routine, random drug screenings to assess treatment compliance and effectiveness.

• Monitor patients’ psychological status and pain diaries to see if other problems are being inappropriately treated with pain medications.

“Universal precautions for chronic pain patients are really about applying sound logic,” Bennett says. Neither Bennett nor Webster feel that any additional universal precautions are needed for breakthrough pain patients beyond what is appropriate for chronic pain patients.

Changing fate of cancer patients Breakthrough pain in cancer patients is related to the severity of cancer, and patients with breakthrough pain are more likely to have poor mood, worse functioning, and higher costs and healthcare utilization, says Portenoy. And while more people with cancer are living longer than when breakthrough pain was first described in the 1970s, the prevalence of breakthrough pain has remained the same: between 30% and 60%. “For a substantial number of patients, breakthrough pain becomes a problem unto itself,” Portenoy says.

When breakthrough cancer pain was first described, most patients were treated in hospitals or palliative care settings. Today, most cancer patients are treated on an outpatient basis and the overall five-year survival rate for all types of cancer has increased to 67% for white patients and 57% for African American patients. Many cancer patients are living for years, even decades, with active disease and pain.

Some cancer patients experience neuropathic pain as a result of chemotherapy and radiation treatments, leaving many clinicians perplexed as to whether these patients are still cancer pain patients. “We need to consider the potential long-term cancer survivor as suffering from a mix of malignant and non-malignant pain, which means that managing his or her breakthrough pain is also a different concept,” says Amy Abernethy, MD, who directs the Duke Cancer Care Research Program in Durham. “Our cancer pain management models haven’t kept step with the changing world of outpatient oncology care.”

Treatment setting now plays a greater factor in managing breakthrough pain in cancer patients. Abernethy says, “The typical cancer pain patient that we understood is still found in the palliative care setting where there is a low risk of addiction and a high need for breakthrough pain management.” Today’s oncology treatment setting has much in common with outpatient pain specialty clinics. “We need to be smart and pull in other interventions besides drugs and help patients achieve coping models that are more applicable over time,” she says, such as exercise/yoga interventions and psychosocial care in addition to medication.

Rapid-acting opioids do still have a valuable role in treating today’s cancer pain patients with breakthrough pain. The best candidates for rapid-onset opioids can afford the additional cost of $200 to $300 monthly, Portenoy claims, and have breakthrough pain episodes that where intensity peaks within 10 minutes, matching the drug pharmacology. Patients who have tried conventional oral short-acting opioids without success (because their pain comes on too fast) are also candidates.

According to Portenoy, perception of risk of addiction in cancer pain patients also needs to be reassessed. “It’s not rational to think that because someone has a tumor that bad things from opioids can’t happen,” he says. “It’s also not rational to think that because someone has noncancer chronic pain, therefore bad things will happen with opioid therapy.”

Recent breakthroughs in breakthrough pain such as recognition in noncancer pain, treatments with rapid-acting opioids, and the evolving picture for cancer patients are changing the medical landscape for chronic pain management. Yet, the field of breakthrough pain is still really in its adolescence, where the main priority is education. Breakthrough pain continues to be unrecognized outside of pain specialists and there is lack of understand about the appropriate management. Portenoy says its starts with all medical professionals: doctors, nurses, pharmacists, and society as a whole. “Breakthrough pain is a component of chronic pain with significant adverse consequences. Clinicians are obligated to ask about it and recognize it. And, if the patient is suffering above and beyond the chronic pain, it demands treatment.”

Heather Haley, MS, is a medical writer based in Cincinnati, OH.