Breakthrough Pain: Just Pain?

Pain. 2016;157(12):2621-2622.

Pain fluctuates, and pain fluctuations are tremendously varied between patients and between clinical circumstances. Opioid analgesic regimes have never been entirely satisfactory in terms of being able to cope with pain fluctuations. Nevertheless, waiting out short painful episodes such as colic or movement-induced bone pain, or waiting until morphine started to work, used to be the norm. Nowadays we think differently, largely because drug development can manipulate opioid onset and offset with the enticing possibility of being able to match analgesia more accurately to pain. The term “breakthrough pain” came about as part of this development, when it became necessary to provide some precision about what was needed to optimize opioid analgesia. As Mercadante and Portenoy describe in their review in this edition of PAIN®, the initial broad definition as a transitory increase in pain that occurs on a baseline of less pain, is now narrowed to an episode of severe pain that occurs in patients receiving a “stable” opioid regime. After much confusion, debate and controversy about what the term breakthrough pain actually means, it is now narrowed to mean pain that emerges for whatever reason despite taking opioids that control pain adequately most of the time. The debate that still remains is whether the base of “stable” opioid makes these episodes of severe pain any less needy of intervention, and whether breakthrough pain is in fact just pain.

Efforts to optimize pain relief for patients with cancer in the 1980s led to the development of 3 new principles—use of extended-release opioids round the clock, titrate to effect, and breakthrough pain. Although intended to improve pain control in patients with cancer, these principles gradually became recommended more widely for chronic pain. Cancer stopped being a rapidly fatal disease, and became a chronic disease, often painful throughout its long course. Now, because the new principles of opioid prescribing were applied for years rather than their originally intended weeks or months, doses of opioids became higher than ever before, as it became necessary to overcome the tolerance associated with continuous and prolonged use.

The United States experience with widespread use of opioids for chronic pain is sobering. As more opioids were used at higher doses in the 2 decades after extended-release opioids were specifically targeted to treat chronic noncancer pain, more prescription opioid abuse and deaths were reported, to the point that prescription opioids produced a public health crisis. In response to this public health crisis, epidemiological, scientific, and clinical data have been collected at an unprecedented rate. These data now leave no doubt that all adverse outcomes for chronic opioid therapy, including but not limited to abuse and death, are more likely to arise when high doses are used. This is worrying enough, but what if at the same time, higher doses are less likely to provide sustained effective analgesia, or worse still, what if they alter and worsen pain? It is one thing if we accept risk and rely on risk mitigation to minimize risk if the benefits are substantial, but quite another if they are not. When as clinicians treating chronic pain, we began to observe that our patients receiving the highest doses of opioids seemed to experience the least relief, we turned to the basic scientists to help us understand what was happening. It seemed that not just tolerance, but hyperalgesia (paradoxical pain sensitization), was interfering with opioids’ ability to provide sustained relief. The science has advanced since those initial clinical observations, making clear the significant overlap and shared mechanisms between the central sensitization that arises as pain becomes chronic, opioid tolerance, and opioid induced pain sensitization. These are changes, according to both clinical and scientific data, that are much more likely to arise when high dose or high potency opioids are used, fentanyl and its derivatives being a case in point because they are both potent and used in high dosage forms. Some of these changes persist long after opioids are discontinued. For some common pain conditions, especially pain that is centrally driven such as fibromyalgia, headache, and nonstructural back pain, high dose and high potency opioids may worsen rather than improve symptoms.

When we manage pain, the ideal is of course that there are no periods of uncontrolled and distressing pain. New opioid formulations were initially developed specifically for the treatment of distressing end-of-life cancer pain, first extended release for round-the-clock administration, then ultrarapid onset/offset to match cancer-related episodic pain, which generally peaks within minutes and persists for only up to an hour. This is a population that relies heavily on oral medication, and as suggested by Mercadante and Portenoy, the new formulations have had, and may continue to have, significant benefits for these patients. But what of long-term pain?—does the breakthrough pain concept, which suggests opioid upon opioid, have any role at all? And are Mercadante and Portenoy right to assert that there is such a role, even for fentanyl? Principles appropriate to end-of-life cancer pain management—use of extended-release opioids round the clock, titrate to effect, and breakthrough pain—led to the high doses that we now believe are harmful and not helpful when pain is chronic. High potency opioids such as fentanyl may be particularly prone to produce tolerance and hyperalgia to say nothing of the strong evidence that rapid onset of opioid effect is a significant risk factor for addiction. Drug trials may show short-term efficacy and safety for breakthrough medication, but they do not inform about long-term outcomes in the general population, as the United States learned from bitter experience. We now have growing evidence that if opioids are used at all for chronic pain, they should not be used by the principles developed for end-of-life cancer pain. When pain is chronic, the best results seem to come when low-risk patients take only immediate-release opioids as needed, or high-risk patients take only extended-release opioids. All these suggest that whatever be their role in the treatment of short-lived pain, the breakthrough pain concept, and rapid onset fentanyl products in particular, do not have a role when pain is chronic.