In the 18th century, the French philosopher Voltaire said, "Doctors are men who prescribe medicines of which they know little, to cure diseases of which they know less, in human beings of which they know nothing...." He also opined that "...it is dangerous to be right on matters on which established authorities are wrong." If he were alive today, writing a tome on pain medicine, it would be easy to imagine Voltaire describing physicians as people who withhold medications of which they know a great deal, to manage painful conditions of which they have learned even more, in human beings who perceive them as knowing nothing, amidst a regulatory climate that scares the hell out of them.
In the 21st century, it is ironic that although we have made significant advances in our understanding of how pain affects the nervous system and continue to develop innovative treatments, many pain sufferers, including dying cancer patients, receive little or no treatment. One possible explanation is the dizzying development of scientific theories of pain physiology, including the different subtypes of pain and the associated improvements in available treatment options, counterbalanced by increasing regulatory scrutiny and limited financial resources for some patients.
Breakthrough pain is a perfect example of the need to understand and treat all of the different pain subtypes. As is typical in pain medicine, breakthrough pain first came to the attention of clinicians in the cancer population. In 1990, Portenoy and Hagen proposed that transient flares of pain in a cancer patient with stable persistent pain treated with opioids be defined as breakthrough pain. However, breakthrough pain is neither specific to cancer pain, nor is it purely an opioid-related phenomenon. Cancer pain often is the catalyst for improving the nomenclature used to describe the different types of pain, and advances in opioid pharmacology often help to define these changes.
The Pain Cascade in Brief
Acute pain follows some sort of injury to the body and generally dissipates when the injury heals. It serves a useful purpose in warning us that deferring treatment may result in life-threatening consequences. For example, a patient with acute appendicitis may complain of sudden, sharp, intense right lower quadrant abdominal pain. Without the pain, the diagnosis may be missed and the appendix could rupture, resulting in tragic consequences. By contrast, chronic pain serves no useful function, persisting beyond the time one would expect normal healing to occur.
Following an injury or other insult to the body, incoming pain signals trigger the release of glutamate, an excitatory neurotransmitter, into the synaptic cleft between nociceptors and dorsal horn cells. Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors on the sodium and potassium channels are activated by acute pain. With prolonged activation, the magnesium plug in the calcium channel is removed, and N-methyl-D-aspartatic acid (NMDA) receptors in the channel are primed for glutamate activation. A cascade of neural events is triggered, leading to the facilitation of neural remodeling and hypersensitization. In other words, and admittedly, more research is needed to demonstrate this; it is possible that undertreatment of acute pain may facilitate the development of chronic pain and cause years of needless suffering by creating changes in the way the nervous system perceives painful impulses, ultimately confusing benign stimuli as being painful, such as in allodynia. Breakthrough pain, which can be viewed as a type of acute pain, may also, in the opinion of this author, facilitate remodeling of the nervous system when not treated appropriately. At the very least, it can certainly cause needless suffering for patients when not identified and managed.
Breakthrough pain is defined as a transient increase in pain of moderate-to-severe intensity, which occurs against a background of persistent pain of mild-to-moderate intensity that has been controlled. It must be differentiated from uncontrolled persistent pain, acute episodic pain, and end-of-dose failure. If a patient has chronic low back pain and is in pain 24 hours per day despite taking a long-acting opioid and appropriate adjuvant analgesics, then adjusting the long-acting medication should be addressed before considering breakthrough pain. With acute episodic pain, there is no persistent pain between flare-ups. For example, a patient may have severe, debilitating migraine headaches 3 days a month, but be fine the rest of the time. In this case, long-acting medications would be unnecessary. End-of-dose failure occurs when a long-acting medication wears off sooner than one would expect, on the basis of the known duration of action of the medication. This can usually be solved by increasing the frequency of administration of the medication. For example, a patient receiving sustained-release morphine, which has a 12-hour duration of action, reports good pain relief for 8 hours, but then begins to decompensate. Adjusting the dose to every 8 hours should be tried before adding other medications.
Breakthrough Pain: Incident and Idiopathic
True breakthrough pain is either incident or idiopathic. Incident pain is predictable. A patient who has just had a total knee replacement may be stable except during physical therapy sessions, which cause a flare-up of pain. Administering short-acting medication preemptively may avoid the flare-ups and allow the patient to participate more fully in his/her therapy. Incident pain can occur with movement, coughing, and increased activity. Some patients tell me they avoid activity because they are afraid this will cause their pain to flare. Knowing they have options to treat these flare-ups can improve functioning.
Breakthrough pain can also be idiopathic, or spontaneous. It can occur randomly and unpredictably with little or no warning, and can be unrelated to activity level or adequacy of the persistent pain treatment. The intensity of breakthrough pain is generally moderate to severe. Onset tends to be rapid, with 43% of patients reporting an onset of 3 minutes or less. The duration of idiopathic breakthrough pain tends to be short. Although variable, some patients report a duration of 20-30 minutes. The frequency averages 1-4 episodes per day. This represents an average, however, so a patient may have days free of breakthrough pain and other days marred by 8 episodes. Also, some patients may experience a more insidious onset and a longer duration of pain. This is why assessment is so important to individualize treatment.
Addressing Breakthrough Pain
After maximizing the treatment of background pain and ruling out end-of-dose failure, I ask my patients the following questions: (1) Do you have pain flare-ups; (2) if yes, how long does it take for you to feel the increase in pain; (3) how long does the increased pain last; (4) are the flare-ups associated with a specific activity, or do they occur randomly; (5) does the increased pain prevent you from doing any activities?
Why bother adding this to a pain evaluation? According to a study by Portenoy and associates, patients with untreated breakthrough pain demonstrate reduced levels of functioning, have greater levels of anxiety and depression, and are less satisfied with their opioid therapy.
Not treating breakthrough pain can even add to economic burdens. Fortner and colleagues studied patients with chronic cancer pain and found that those who had breakthrough pain incurred costs 5 times higher than patients without breakthrough pain. The greater costs were primarily related to hospitalizations for uncontrolled pain, emergency department visits, and unscheduled office visits. Although current economic data reflect the experience of patients with cancer, I recently participated as an investigator in a study examining the prevalence and impact of breakthrough pain in patients with noncancer pain. The data are still being analyzed, but this illustrates the point that breakthrough pain is not just a cancer-related phenomenon.
Managing Breakthrough Pain
The optimal treatment of pain should employ both pharmacologic and nonpharmacologic approaches, such as interventional pain management, cognitive behavioral therapy, and biofeedback. The World Health Organization analgesic ladder is still used to the pharmacologic treatment of pain. Nonopioids, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and acetominophen, are used to treat mild pain. The guidelines recommend opioids for moderate-to-severe pain. Thus, the pain intensity should drive the choice of medication when using the ladder. Some clinicians erroneously believe that they must begin with a nonopioid, even when the patient suffers severe pain.
Acute pain should be treated early and appropriately to avoid both needless suffering and to prevent possible remodeling of the central nervous system. Breakthrough pain should also be addressed on the basis of the results of the aforementioned evaluation. Some clinicians attend to breakthrough pain by increasing the dose of long-acting medication. This strategy may cause sedation and side effects, because the patient is now being exposed to a greater medication load. They are also receiving pain medication at times when they are not experiencing pain. Ideally, patients should be placed on long-acting medications to control their persistent pain and shorter-acting medications to control breakthrough pain.
Individualizing the Approach
The recommendation for dosing breakthrough medication at 10% to 15% of the daily long-acting dose does not seem to match clinical experience. Some patients may have more breakthrough pain relative to persistent pain. The treatment must therefore be individualized and based on proper evaluation. For a patient whose breakthrough pain comes on gradually and lasts 45 minutes to an hour, conventional, hydrophilic, shorter acting opioids (such as oxycodone, hydrocodone, morphine, or hydromorphone) may be fine. If a patient is taking sustained-release oxycodone for persistent pain and the characteristics of his/her breakthrough pain episodes match the pharmacologic profile of shorter acting oxycodone, then that would be a clinically feasible combination.
For the 43% of patients with an onset of breakthrough pain in less than 3 minutes and a duration of 20-30 minutes, the shorter acting, hydrophilic medications only begin to work when the pain has already dissipated. And we are, once again, subjecting the patient to unnecessary medication. In my practice, I've been able to dramatically reduce some patients' total opioid doses by properly addressing their previously untreated or mistreated breakthrough pain. The ideal breakthrough medication for this subset of patients should have a rapid onset, short duration of effect, minimal side effects, and be easy to use (noninvasive). Oral transmucosal fentanyl is the only medication that fits this profile without requiring patients to self-inject opioids at home, a practice I generally try to avoid. US Food and Drug Administration (FDA)-approved for management of breakthrough pain in non-opioid-naïve cancer patients, this short-acting formulation takes advantage of the oral transmucosal route of delivery. The oral mucosa is highly vascularized and very permeable, which, combined with the lipophilic nature of fentanyl, allows the agent to enter the bloodstream rapidly and directly without hepatic and intestinal first-pass metabolism. Rapid onset of action is achieved without invasive methods.
Some patients say that they feel "empowered" to have a tool that can give them rapid relief that in the past could only be achieved by a trip to the emergency department for an injection. It is also the only way to use fentanyl for breakthrough pain when patients are using the fentanyl transdermal patch. Some clinicians, including myself, believe that if persistent pain is responsive to fentanyl, then the likelihood is that the same will hold true for breakthrough pain. This of course entails off-label use at times, a practice not uncommon in pain medicine. Concerns about abuse, diversion, and addiction are certainly valid; however, any controlled substance can potentially be abused. Proper patient selection, monitoring, use-of-treatment agreements, and toxicology screens can help to reduce these risks. This medication provides the opportunity to ask patients to bring in the used sticks, which can be counted to help determine that the medication is not being diverted.
Some patients may be able to use nonopioids, such as NSAIDs, for breakthrough episodes or tramadol, a centrally acting analgesic with weak mu-receptor affinity that also inhibits the reuptake of norepinephrine and serotonin. However, because breakthrough pain is at least moderate in intensity by definition, opioids are the most likely pharmacologic intervention.
Other strategies that can be helpful for breakthrough pain episodes include relaxation training, hypnosis, and cognitive behavioral therapy, although scientifically controlled studies have not validated these techniques in breakthrough pain. Patient education and family involvement are critical and should be addressed early in treatment.
In summary, acute pain should be managed early and effectively both for proper medical care and to help prevent remodeling of the central nervous system, which may facilitate the development of persistent pain. Breakthrough pain is a valid type of acute pain that occurs commonly in patients with persistent pain, and it has to be managed. Increasing the dose of long-acting opioids often exposes the patient to needlessly high doses of medication and can result in sedation, constipation, and other side effects. Some physicians believe that prescribing only long-acting opioids will reduce their liability; however, addicts can crush, liquify, inject, and snort long-acting opioids, essentially converting them to rapid-acting agents. Treatment should therefore be individualized on the basis of the nature of an individual's breakthrough pain. Optimally, however, medication should be noninvasive, have a rapid onset, and have a relatively short duration of effect.
- Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence and characteristics. Pain. 1990;41:273-281. Abstract
- Burstein R, Yamamura H, Malick A, Strassman AM. Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brain stem trigeminal neurons. J Neurophysiol. 1998;79:964-82. Abstract
- Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: characteristics and impact in patients with cancer pain. Pain. 1999;81:129-134. Abstract
- Fortner BV, Okon TA, Portenoy RK. A survey of pain-related hospitalizations, emergency department visits, and physician office visits reported by cancer patients with and without history of breakthrough pain. J Pain. 2002;3:38-44. Abstract