What is breakthrough pain, or "BTP"?
In patients who have moderate to severe pain, two components are usually present: persistent pain (lasting 12 or more hours/day) and breakthrough pain (BTP), a transitory flare of pain of moderate to severe intensity occurring on a background of otherwise controlled pain.^1-3

BTP has been reported in up to 86% of patients treated with around-the-clock (ATC) medications for their persistent pain⁴. In one survey, patients experienced an average of 4 episodes of BTP per day². Based on the results from this same survey, the onset of BTP is often sudden, reaches maximal intensity within 3 minutes, and lasts for a median duration of 30 minutes.²

There are 3 types of breakthrough pain - spontaneous, incident, and end-of-dose failure. The etiology of BTP may be related to a disease or condition, or to its treatment.

How is BTP different from persistent pain?
It is critical that breakthrough pain first be distinguished from uncontrolled persistent pain.1 To clarify this concept, leading investigators in the field of pain management have defined persistent pain as that experienced for 12 or more hours per day.²

Breakthrough pain has been defined as a transitory exacerbation of moderate to severe pain occurring in patients against a background of persistent pain otherwise controlled with chronic opioid therapy.^2,5

Specific characteristics that further define breakthrough pain include its relationship to the fixed opioid dose for the persistent pain, temporal features, precipitating events, and predictability.^1,2

What is the relationship of BTP to a fixed opioid dose?
Spontaneous and incident breakthrough pain episodes need to be differentiated from the type of pain resulting from end-of-dose failure-that is, pain appearing with greater frequency at the end of the dosing interval of the around-the-clock opioid medication. This type of pain is marked by a more gradual onset and prolonged duration than other breakthrough pain episodes, and can be linked to the dissipating analgesic effect of the around-the-clock medication used for persistent pain. Pain resulting from end-of-dose failure is often best managed by adjusting the dose of the around-the-clock medication.

What are the temporal characteristics of BTP?
Breakthrough pain is characterized by temporal features, including the onset, duration, and frequency of each episode. The onset of pain is often sudden, reaching maximal intensity within 3 minutes 43% of the time as observed in one survey.² And while the duration may vary, the median duration in this same survey was 30 minutes, though some pains lasted for several hours.² Additionally, patients experienced an average of four episodes per day.²

What are the precipitating events and predictability of BTP?
Episodes of breakthrough pain may be either spontaneous, occurring without a precipitated event, or precipitated, initiated by a volitional or nonvolitional event.²

Precipitated pain is referred to as incident pain when it is volitional-i.e., induced by an action of the patient, such as walking, swallowing, turning, lifting, coughing, urination, or defecation.^1,6 Breakthrough pain may also be related to identifiable but nonvolitional events in which the patient does not knowingly initiate the activity-e.g., flatulence, myoclonic jerking, or stress.²

As patients learn that certain actions cause breakthrough pain, these episodes can be anticipated and may allow patients and physicians to either prepare a treatment response or to treat prophylactically. However, not all precipitated pains are predictable; for example, pain related to myoclonic jerking is precipitated but not predictable.

What is the etiology of BTP episodes?
The etiology of breakthrough pain can be related to a disease or condition, or to its treatment.² Although specific etiology may not explain manifestation as breakthrough pain, determination is essential for effective management.

What is the prevalence of BTP?
The prevalence and characteristics of breakthrough pain have been evaluated in a number of studies in which sampling procedures such as inclusion criteria, chronic pain therapy, and severity of pain have varied considerably.^3,7 Because breakthrough pain was not defined similarly in each of these studies,⁸ the reported prevalence of breakthrough pain ranges from 19%9 to 84%.³

In one of the few prospective studies designed to evaluate breakthrough pain, 90 inpatients consecutively referred to a pain service in a major cancer center were evaluated over a 3-month period.² Of these patients, 70 achieved the initial criterion of stable opioid dosing for 2 or more days, and 90% of this group reported persistent pain of moderate intensity or less for greater than 12 hours per day. Of the latter group, 63% described one or more episodes of breakthrough pain in the preceding 24 hours.

The 51 breakthrough pain episodes reported by patients were analyzed by their defining characteristics. The majority were found to be related to the tumor and located at the same site as the continuous pain,² suggesting that the breakthrough pain was most likely an exacerbation of the existing pain. Precipitants to pain were identified in 55% of the pain episodes. Pain onset or marked worsening of pain occurred at the end of the dosing interval in only 29% of pains, indicating that the majority of breakthrough pain episodes were not associated with the failure of the around-the-clock scheduled opioid analgesic.²

While the frequency of breakthrough pains reported in the literature is somewhat variable, it is generally accepted that patients will experience one to four episodes per day.^2,3,10-12 In the key study cited above, the median number of breakthrough pains over a 24-hour period was four, with 12 patients experiencing seven or more breakthrough pains during that period. Forty-three percent of the pain episodes had an onset within 3 minutes, and the median duration of the pains was 30 minutes (range 1-240 minutes).²

What are the limitations of previous treatments for BTP?
The traditional approach to the management of chronic cancer pain is illustrated by the World Health Organization (WHO) ladder .¹³ The opioid dose capable of maintaining adequate analgesia for persistent pain may be insufficient during breakthrough pain episodes.⁹ While this is not surprising, it emphasizes the importance of direct, effective treatment of breakthrough pain.

(Adapted from Reference 13)

Type of Drug
NSAIDs and adjuvant drugs may be used at any stage in appropriate patients to enhance the efficacy of analgesia, treat concurrent symptoms that exacerbate pain, or provide independent analgesic activity for specific types of pain.

The use of adjuvant therapies, as well as other drugs designed to reduce the frequency of pain-precipitating events (e.g., antitussives, laxatives, or antidiarrheals, antiperistaltic drugs, or agents that reduce muscle spasm), has usually been observed to indirectly improve, but not eliminate, breakthrough pain¹⁴. Consequently, pharmacologic therapy for breakthrough pain has typically consisted of the use of an analgesic drug, usually a short-acting opioid, on an as-needed basis, to supplement the fixed opioid schedule. In the cancer population, short-acting morphine sulfate, oxycodone, and hydromorphone have been commonly used for this purpose.

Until recently, however, no controlled clinical trials have been conducted to evaluate the pharmacology and efficacy of the drugs and formulations conventionally used to manage breakthrough pain. Nonetheless, the limitations of these agents have become clinically evident. For many patients, the onset of action of a so-called short-acting opioid may still be too slow to effectively treat breakthrough pains.¹⁴

Dose
Typically, the dose of the supplemental medication used has been based on a fixed percentage of the scheduled opioid regimen [around-the-clock], and like the regularly scheduled opioid regimen, the supplemental dose was typically titrated upward until side effects precluded its use. Despite attempts to establish this relationship between dosages more clearly, treatment recommendations have been widely divergent, including the use of 5%-50% of the total daily dose every 1-12 hours as needed.^3,15-18 This inconsistency may reflect the lack of randomized controlled trials on the management of breakthrough pain.

Side Effects
In patients with breakthrough pain related to the around-the-clock interval, upward titration or an increase in dosing frequency of the scheduled around-the-clock opioid to optimal levels is critical and may obviate the problem¹⁴. However, in the many patients with breakthrough pain not related to the around-the-clock dosing interval, attempts to cover these pain episodes by increasing the dose of long-acting analgesics may result in unacceptable side effects (Figure 3).¹⁹

Risk of overmedication.

Common adverse effects of opioid analgesics include constipation, nausea, sedation, and confusion; less common effects include urinary retention, delirium, myoclonic jerks, seizures, and respiratory depression.²⁰

Route of Administration
Previously available oral, rectal, or sublingual analgesic formulations have demonstrated erratic absorption characteristics and other properties that make them less than optimal for the management of breakthrough pain.¹⁹

Orally administered opioids offer convenience, simplicity, and cost-effectiveness. But for many patients, the onset of action of an oral supplemental opioid may be too slow to effectively treat the breakthrough pain.¹⁴ Furthermore, patients with dysphagia, whose oral intake may be limited, or gastrointestinal dysfunction, leading to unreliable drug absorption, may not benefit from oral medication.
Physical and psychological issues often make the rectal route of administration unsuitable for patients with breakthrough pain. The onset of action of rectally administered drugs is relatively slow, unpredictable, and the method is inconvenient for frequent use.¹⁷

While sublingual formulations of opioids would appear to provide an ideal route for rapid absorption, only a few products actually work in this manner. Clinical studies have demonstrated that sublingual morphine actually is poorly absorbed.²¹ The time to maximum concentration was significantly delayed due to poor lipophilicity. Due to the extremely bitter taste, all of the patients in the study found the sublingual route an unpleasant way to receive their opioid treatment.²¹

Intramuscular injection of opioids is painful, offers no advantages, and is rarely indicated, for example, in patients with cancer.²²

Although faster acting than other routes of administration, intravenous opioid therapy is invasive, restrictive, costly, and often not practical when breakthrough pain episodes demand it. In patients receiving continuous subcutaneous or intravenous infusion, the supplemental dose for breakthrough pain may be provided by the same route, and expedited by patient-controlled analgesia systems. However, subcutaneous infusion pump systems are expensive and invasive¹⁷ and can restrict the patient's sense of independence and autonomy.

The use of multiple routes of administration for combinations of the WHO ladder and adjuvant analgesic drugs constitutes an option for the management of breakthrough pain.⁶

Timing of Administration
Timing of administration of the supplemental oral opioid dose depends on the predictability of the breakthrough pain and the pharmacokinetic profile of the supplemental medication. For predictable pain, the dose of currently available oral opioid medications must be taken 30 minutes to 1 hour prior to the precipitating event. For patients with unpredictable breakthrough pain, a supplemental dose can only be taken after pain onset, necessitating a rapid onset of action to provide adequate relief. However, many current medications for breakthrough pain do not act quickly enough (Figure 4).

Current treatment approach to breakthrough pain.

Onset of Action
Because not all breakthrough pains are precipitated or predictable, effective treatment necessitates the use of an agent with a more rapid onset of action than that provided by traditional short-acting oral medications (e.g., short-acting morphine or an oxycodone) commonly used for this purpose.

In summary, a treatment option that is an oral analgesic with a sudden onset and relatively short duration, as theoretically demonstrated in Figure 5, would address many of the needs specific to breakthrough pain.¹⁴

The preferred treatment.

References:
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