Breakthrough pain (BTP) is experienced by many patients being treated with opioids for the management of chronic persistent pain. Control of BTP has been problematic since, until recently, the pharmacokinetics of older treatments was largely incompatible with the onset and duration of these pain episodes. Newer agents are now available that better approximate the timing of BTP episodes, and their use is increasingly being integrated into opioid-based pain management strategies. Successful management of BTP can improve treatment satisfaction and the quality of life of patients with chronic persistent pain of both cancer and noncancer origins. This article reviews the types of BTP, the therapeutic options available to manage BTP, and the tools designed to detect and minimize the risk of aberrant drugrelated behaviors potentially associated with opioid medications.
(Am J Manag Care. 2008;14:S123-S128)
Breakthrough pain (BTP) is experienced by many patients being treated with opioids during the management of chronic persistent pain. As described in the previous article, 4 types of BTP are recognized: end-of-dose (EOD) failure; incident, predictable (IP); incident, unpredictable (IUP); and idiopathic/spontaneous (IS). This review will outline the pharmacologic interventions available for management of the different types of BTP.
Opioids are often prescribed for the management of chronic pain of both cancer and noncancer origins. Long-acting opioids, prescribed for control of the persistent, baseline component of chronic pain, are characterized by a slow onset of action and a pharmacokinetic profile with minimal peaks and valleys that result in stable blood levels over the dose period.1 This class of opioids includes transdermal fentanyl; methadone; morphine controlled-release (CR), sustained-release, and extendedrelease (ER); oxycodone CR; tramadol ER; and oxymorphone ER.
Short-acting opioids, which include codeine, hydrocodone, hydromorphone, morphine, oxycodone, tramadol, and oxymorphone, are generally recommended for the treatment of acute pain as their onset of action is faster than the long-acting opioids. This class of opioids has limited utility for the treatment of BTP because the onset of efficacy can be more than 30 minutes, whereas median time to maximum intensity of BTP is about 10 minutes.2 Therefore, to treat BTP, more rapid-acting agents are needed.
Short-acting, immediate-onset opioids are available for the treatment of BTP. The pharmacokinetic profile of these medications, which are formulations of fentanyl designed for rapid oral absorption, most closely mirrors the temporal pattern of BTP episodes.
Before deciding on a strategy for control of BTP, it is important to consider whether the opioid therapy being utilized to control the persistent component of chronic pain is adequate. In general, frequent episodes of BTP are probably indicative of inadequately treated persistent pain. When a patient experiences more than 4 BTP episodes per day, reassessment of the cause of pain and/or approach to management of chronic pain is warranted.3 Effective treatment of BTP requires a strategy tailored for the individual patient that considers the cause and type of BTP episodes. Although short-acting, immediate- onset opioids are the primary therapy, supplemental nonpharmacologic interventions are often also useful. These include physical therapy, behavioral modification, and psychological approaches such as cognitive behavioral therapy.4,5
Another consideration that has been shown to affect the patient’s acceptance of a particular medication is the route of administration. In a study of 100 patients with chronic cancer-related pain, participants were asked to complete a questionnaire concerning the acceptability of 9 administration routes (oral, rectal, nasal, sublingual, transmucosal, inhaled, and subcutaneous, intramuscular, and intravenous injection) for control of mild-to-moderate and severe BTP. The reason for unacceptability and each patient’s experience with each route were also collected. Results suggest that the oral route is most acceptable, whereas the relatively long time to onset of effectiveness of oral medications was the main reason for unacceptability. The rectal route was least acceptable. When injections are compared, the subcutaneous is preferred rather than intramuscular or intravenous. In general, acceptability is rated lower when the patient has less experience with a particular route, which is often the case with the newer routes of administration, such as nasal, transmucosal, or inhaled.6
Treatment Options for BTP
When a patient consistently reports occurrence of BTP episodes primarily at the end of the opioid dose period, EOD failure should be suspected. In this subtype of BTP, circulating levels of the opioid prescribed for the baseline component of chronic pain are no longer sufficient for adequate analgesia. The following pain management algorithm can provide relief without the need for additional BTP-specific medications: (1) increase the dose of the long-acting opioid currently being used; (2) if unacceptable side effects occur at this higher dose, use a lower dose (split the higher dose) and administer more frequently; (3) if EOD BTP is occurring near the end of a specific dose period (eg, the morning dose), asymmetric dosing may be of benefit—in this example, a higher dose would be administered in the morning versus evening; (4) rotate the patient to an alternate long-acting opioid and monitor BTP incidence.3
IP BTP is characterized by episodes associated with certain activities such as physical exertion or stressful circumstances. Patients can often predict the onset of this subtype of BTP and, if onset of pain is slow enough (~30 minutes), prevention of an episode is possible by administration of a short-acting opioid before an attack.3
Patients experiencing IUP BTP or IS BTP cannot predict the onset of an episode and therefore cannot be pretreated. Treatment of these subtypes of BTP can be problematic and requires an agent with a very fast onset of action—even the short-acting opioids are unsuitable here since their onset of action occurs in 15 to 20 minutes, peaks at 30 to 45 minutes,7 and lasts 3 to 6 hours, whereas BTP typically lasts 30 to 60 minutes.8 The time course of activity of immediate-onset opioids best approximates that of BTP episodes, making them the agents of choice for control of IUP- and IS-type BTP.2,9,10 The US Food and Drug Administration (FDA)-approved rapid-onset opioids have the following advantages: fentanyl is used, which is highly lipophilic and rapidly crosses the buccal membrane and bloodbrain barrier; their short half-life mirrors the time course of BTP; and they are orally administered.
The 2 short-acting, rapid-onset opioids currently FDA approved for treatment of BTP are oral transmucosal fentanyl citrate (OTFC) and fentanyl buccal tablet (FBT). Both of these medications were originally studied for control of BTP in patients already on opioids for the management of cancerrelated pain. Further studies and clinical experience in opioid-treated patients suffering from chronic persistent pain of noncancer origins have also confirmed their usefulness for treatment of BTP in this patient population. The general properties of these medications are compared in the .11-15
OTFC is a formulation of fentanyl citrate embedded in a sweetened lozenge on a stick that dissolves in the mouth, delivering part of the dose through the sublingual and buccal mucosa. A randomized, double-blind, dose-titration study of OTFC was carried out in 62 adult patients being treated with transdermal fentanyl for persistent pain associated with various cancers, most commonly lung and prostate. A safe and effective dose of OTFC was found for 76% of patients, and no meaningful relationship was detected between the opioid regimen being used for relief of baseline pain and the dose of OTFC effective for control of BTP.16
In a second randomized, double-blind, placebocontrolled trial of 92 patients with cancer-related pain suffering at least 1 episode of BTP per day, OTFC was significantly superior to placebo as measured by changes in pain intensity scores and overall pain relief. Also, use of rescue medication was significantly less (15% vs 34%; P <.0001) in the OTFC group compared with placebo.7 When compared with morphine sulfate immediate-release in a randomized, double-blind, crossover trial of 134 cancer patients, OTFC was superior for management of BTP by pain intensity differences, pain relief, and global performance of medication scores.10
A recent analysis of data from 3 trials of OTFC for BTP in cancer patients (N = 188) suggests that the dose of OTFC should be individualized according to each patient’s response for BTP, and this titration strategy should be separate from that used for the medication prescribed for the treatment of the persistent component of their pain.17 Dosing guidelines have been developed for OTFC based on clinical experience for both cancer- and noncancerrelated pain.18
FBT is designed to enhance the absorption of fentanyl through the buccal mucosa using an effervescent reaction that increases the rate of tablet dissolution and membrane permeation. When compared with OTFC, a greater proportion of fentanyl is absorbed transmucosally in FBT (48% vs 22%), and the time to maximum plasma concentration is about half that of OTFC.
In a randomized, placebo-controlled study of 123 opioid-treated cancer patients, pain intensity differences, pain relief, and global performance of the medication were significantly greater for FBT than placebo at all time points.2
A 3-month interim analysis was undertaken of a 1-year, open-label safety trial of FBT in patients with cancer-related BTP. In this study, 158 patients being treated with morphine for control of persistent pain received at least 1 dose of FBT; mean exposure to FBT was 70.7 days. Most frequently occurring adverse events (AEs) were typical of opioids—nausea, vomiting, dizziness, fatigue, and headache—while the most common serious AEs of pneumonia and dehydration were expected in a population of cancer patients.
Discontinuation because of AEs was 20%, with the most frequent reasons reported as uncontrolled persistent pain, metastatic lung cancer, and nausea. Oral mucosal AEs, including ulceration, erythema, and pain, led to discontinuation by 2 patients, and sedation was reported by 1 patient as the reason for discontinuation. There were no reports of respiratory depression or tablet aspiration.19
The efficacy of FBT for control of BTP in opioidtreated patients with chronic pain of noncancer origins was studied in 2 randomized, placebo-controlled trials. One trial included 102 patients suffering from chronic neuropathic pain of various etiologies, most commonly diabetic peripheral neuropathy, traumatic injury, and complex regional pain syndrome. An effective dose of FBT was identified in 80 patients in the open-label titration phase of the study, with 79 entering the double-blind phase. The primary efficacy measure was the mean sum of pain intensity differences for the 60-minute period postdose (SPID60), which was significantly greater in patients treated with FBT compared with those in the placebo group (9.63 vs 5.73; P <.001). Significant differences in pain intensity were recorded as early as 10 minutes postdose (0.74 vs 0.43; P <.05). Most common AEs, typical of those seen in opioid trials, included nausea, dizziness, somnolence, and vomiting.11
FBT was also studied in 105 patients with chronic low back pain, of which an effective dose was identified for 84 patients in the open-label titration phase and 77 patients in the double-blind phase. SPID60 scores were statistically significantly greater for FBT treated patients compared with placebo (P <.0001), with significant differences in pain intensity and pain relief starting at 10 and 15 minutes, respectively. FBT was well tolerated with AEs typical of those seen with opioids.12
In a 4-month interim analysis of an ongoing study for FBT in 94 patients with chronic pain of mixed etiologies, FBT was found to be safe and well tolerated. Nausea and dizziness were the most common AEs; 3 patients discontinued the study because of AEs, and 22 patients experienced application-site AEs such as pain, irritation, and ulceration.20 It is important to note that both FBT and OTFC are approved for use only in patients already on a prescription opioid for chronic pain and who have been shown to tolerate opioids. Dosing guidelines must also be carefully followed to prevent a potential overdose.13,21 Serious AEs or death may result when these factors are not considered.
Investigational Pharmacotherapies for BTP
A number of investigational opioid- and nonopioid- based medications are at various stages of development for the treatment of BTP. Midazolam,22 a self-administered intranasal formulation of ketamine,23 and self-administered inhaled nitrous oxide24 are among the nonopioid group.
Novel formulations of opioids that use various routes of administration are also under study for BTP, including oral methadone25; sublingual buprenorphine26; intranasal fentanyl,27,28 morphine,29,30 and sufentanil31; sublingual sufentanil32,33 and methadone34; and subcutaneous35 and intravenous morphine.36 In addition, BEMA fentanyl, which is formulated for transbuccal delivery as a dissolvable polymer disc, is also under investigation.37
Identifying and Monitoring Risk of Opioid Abuse
Effective therapies are available to treat the BTP commonly suffered by patients being treated with opioids for chronic pain. It is important to identify the subtype of BTP to determine the best strategy for treatment of an individual’s pain and achieve improvement in the quality of life for these patients.3,46 Short-acting, immediate-release opioids such as FBT and OTFC are an important component of therapy for certain types of BTP, along with appropriate nonpharmacologic interventions. As with any use of opioids, it is important to monitor abuse and take appropriate steps to correct such behavior.
Authorship Affiliation: Professor of Psychiatry and Adjunct Professor of Neurological Surgery and Anesthesiology, Miller School of Medicine at the University of Miami, FL.
Author Disclosure: The author reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.
Authorship Information: Concept and design; acquisition of data; drafting of the manuscript.
Address Correspondence to: David A. Fishbain, MD, Professor of Psychiatry and Adjunct Professor of Neurological Surgery and Anesthesiology, Miller School of Medicine at the University of Miami, 304A Dominion Tower, 1400 NW 10th Ave, Miami, FL 33136. E-mail: DFishbain@med.miami.edu.
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