Pharmacotherapy for Breakthrough. Cancer Pain. Sebastiano Mercadante1,2. 1 Pain Relief and Supportive Care Unit, La Maddalena Cancer Center, Palermo, ...
Drugs 2012; 72 (2): 181-190 0012-6667/12/0002-0181/$55.55/0
REVIEW ARTICLE
ª 2012 Adis Data Information BV. All rights reserved.
Pharmacotherapy for Breakthrough Cancer Pain Sebastiano Mercadante1,2 1 Pain Relief and Supportive Care Unit, La Maddalena Cancer Center, Palermo, Italy 2 Palliative Medicine, Department of Anesthesia and Intensive Care, University of Palermo, Palermo, Italy
Contents Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Methods of Literature Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Pharmacological Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Non-Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Oral Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Parenteral Opioids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 Rapid Onset Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.1 Oral Transmucosal Fentanyl Citrate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.2 Fentanyl Buccal Tablet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.3 Sublingual Fentanyl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.4 Intranasal Fentanyl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.5 Fentanyl Buccal Soluble Film . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Abstract
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Breakthrough pain (BTP) is a transient exacerbation of pain that occurs either spontaneously, or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain. The principal pharmacological treatment of BTP is represented by the administration of opioids as needed. Oral opioids have traditionally been the only available drugs for BTP. However, the onset and duration of action of oral opioids such as morphine or oxycodone may not be suitable for treating many episodes of BTP that are of short onset and duration. Transmucosal administration of lipophilic substances has gained a growing popularity in recent years due to the rapid effect, clinically observable 10–15 minutes after drug administration, and the non-invasive form. Different technologies have been developed to provide fast pain relief with potent opioid drugs such fentanyl, delivered by non-invasive routes (rapid onset opioids, ROOs). All the studies performed with ROOs have recommended that these drugs should be administered to opioidtolerant patients receiving doses of oral morphine equivalents of at least 60 mg. These preparations, including oral transmucosal fentanyl citrate, fentanyl buccal tablet, sublingual fentanyl, intranasal fentanyl spray, fentanyl-pectin nasal spray and fentanyl buccal soluble film have shown better efficacy than placebo or oral opioids. Long-term studies have confirmed their efficacy and safety.
Mercadante
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1. Introduction Breakthrough pain (BTP) is commonly described as a transient exacerbation of pain that occurs either spontaneously, or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain.[1] BTP is characterized by a typical temporal pattern which includes a short onset (generally a few minutes) and a short duration (30–90 minutes). While there are slight differences with previous definitions,[2-4] all stress the transient nature of BTP against a background of stable and otherwise controlled baseline pain. About 65% of cancer patients experience episodes of BTP, the incidence varying according to the population surveyed, setting and the definition of BTP used.[5-7] BTP is associated with a significant negative impact on both quality of life (including activities of daily living, sleep, social relationships and mood) and medical outcomes.[3] Currently, the therapeutic options for the management of BTP are relatively limited, and principally reside with the use of drugs as needed. The aim of this review was to analyse existing data of the pharmacological methods for the management of BTP. 2. Methods of Literature Review A systematic literature search on PubMed, MEDLINE and EMBASE electronic databases was carried out from each database for the last 12 years, from January 1999 to 30 June 2011; text words and MeSH/EMTREE terms were ‘breakthrough pain’ AND ‘cancer’. A hand search of the reference lists of identified papers was also performed. Studies were included if prospective, comparative, performed in adult patients with chronic cancer pain, containing data about drugs used for the management of BTP and written in the English language. Only papers providing clinical data were included and efficacy and safety issues were examined. Pharmacokinetic studies were excluded, unless to describe the principal characteristics of the drugs. Long-term studies, although not comparative, were also included to evaluate safety and tolerability. ª 2012 Adis Data Information BV. All rights reserved.
3. Pharmacological Treatment 3.1 Non-Opioids
The intermittent use of a nonsteroidal antiinflammatory drug (NSAID) may be effective in some BTPs, as these drugs have proved to be very useful in improving basal analgesia, possibly preventing or limiting the occurrence of BTP. Despite the widespread use of anti-inflammatory agents or paracetamol in cancer pain management, no data have been published for the management of BTP, even in previous decades when a few opioids were available for this purpose. 3.2 Oral Opioids
Until a decade ago, oral opioids were the only available drugs for BTP. Oral opioids, particularly oral morphine, have been the mainstay approach in doses proportional to opioid doses used for background analgesia.[8] However, the onset and duration of action of oral opioids such as morphine or oxycodone may not be suitable for treating many episodes of BTP which are of short onset and duration. Pharmacokinetic studies have suggested a poor correlation of their analgesic effect with the dynamics of a typical BTP episode.[9] The characteristics of oral opioids used for BTP are described in table I. The existing studies were performed to evaluate the effectiveness of new opioid formulations in comparison with oral morphine. Both oral transmucosal fentanyl citrate (OTFC) and oral morphine were titrated up to an effective dose in patients receiving 60–1000 mg of oral morphine equivalents or 50–300 mg/h of transdermal fentanyl. Ninety-three ambulatory patients, successfully titrated, were treated in a double-blind, double-dummy fashion with either OTFC and or oral morphine. Pain intensity (PI) scores at 15, 30, 45 and 60 minutes were higher with oral morphine than OTFC, and PI differences (PID) across all time points also significantly favoured OTFC. Similarly, pain relief (PR) scores were significantly higher for OTFC than oral morphine at each time point. Adverse effects were those commonly reported with opioid therapy.[10] Drugs 2012; 72 (2)
Drug Management of Breakthrough Cancer Pain
Table I. Characteristics of opioids used for breakthrough pain Opioid
Analgesic onset (min)
Availability (%)
Dwell time (min)
Oral morphine
30–45
30
NA
Oral oxycodone
30–45
40–50
NA
OTFC
15
50
15
FBT
15
65
15
SLF
15
70
2
INFS
5–10
70–90
NA
FPNS
5–10
70–90
NA
FBT = fentanyl buccal tablet; FPNS = fentanyl pectin nasal spray; INFS = intranasal fentanyl spray; NA = not applicable; OTFC = oral transmucosal fentanyl citrate; SLF = sublingual fentanyl.
More recently, oral oxycodone was compared with fentanyl buccal tablet (FBT). Opioid-tolerant patients were titrated up to an effective dose for both drugs. In 180 patients successfully titrated, PID at 15 minutes and secondary efficacy measures, including PID at 5 minutes and PR at 10 minutes, summed pain intensity differences at 30 minutes (SPID30) and at 60 minutes (SPID60), were more favourable with FBT than with oral oxycodone. Also, FBT was preferred by 52% of patients and oxycodone by 33%. Adverse effects with both study drugs were generally typical of opioids and the majority of them occurred during dose titration.[11] A formulation of effervescent oral morphine has been developed. The effervescent composition comprises a mixture of stable morphine-containing basic granules and acidic granules, which are in physical contact with one other. Together with a source of carbonate and a physiologically acceptable acid, there is a reaction with carbonate in the presence of water, releasing carbon dioxide. Because of the increase in pH within the effervescent solution, it is suggested that the rate of absorption through the gastrointestinal tract is facilitated, promoting faster pain relief. In an open-label safety and efficacy study, effervescent morphine in starting doses of 20 mg was given to 76 opioid-tolerant patients with chronic cancer pain for the management of BTP. An additional dose of 20 mg was allowed after 10 minutes up to a maximum of four tablets for a single BTP episode. No close correlation was found between effective BTP dosing and the maintenance dose of morphine. Efficacy and ª 2012 Adis Data Information BV. All rights reserved.
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adverse effects were compared to those obtained with normal-release morphine in a preceding runin period. The mean time to achieve sufficient pain relief was significantly shorter than with normalrelease morphine (13 vs 27 minutes), with no differences in adverse effects.[12] 3.3 Parenteral Opioids
As pain relief is usually required urgently, routes of administration designed to deliver drugs rapidly are often chosen. Many cancer patients have a port system that can be used for administering drugs in a rapid way to overlap the temporal pattern of BTP. Moreover, in some acute settings an intravenous line is a rule. Intravenous morphine (IVMO) is an effective method to provide fast analgesia for BTP, providing immediate and total availability of drugs. In a comparative study, IVMO and OTFC were given for BTP in doses proportional to the basal opioid regimen. Twenty-five patients completed 53 couples of BTP events, each randomly treated with IVMO or OTFC. Patients were not blinded. IVMO was significantly more effective than OTFC 15 minutes after administration, while no differences were found at 30 minutes. The outcome was independent of the opioid doses used for background analgesia. Adverse effects were comparable and never troublesome, even in patients receiving high BTP doses.[13] 3.4 Rapid Onset Opioids
Transmucosal administration of lipophilic substances has gained a growing popularity in recent years due to the rapid effect, clinically observable 10–15 minutes after drug administration, and the non-invasive form. Different technologies have been developed to provide fast pain relief with potent opioid drugs such as fentanyl, delivered by non-invasive routes. Fentanyl is a potent and strongly lipophilic drug, which passes easily through the mucosa and then across the blood-brain barrier to provide fast analgesia. All the studies performed with rapid onset opioids (ROOs) have recommended that these drugs should be administered to opioid-tolerant patients receiving doses of oral morphine equivalents of at least 60 mg. The characteristic of ROOs used for BTP and clinical Drugs 2012; 72 (2)
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Table II. Controlled studies of rapid onset opioids Study
Patients (n)
Design
Outcome
Adverse effects
Coluzzi et al.,[10] 2001
93
OTFC vs oral morphine; doubleblind, double-dummy, randomized, multiple crossover
PI, PID, PR and global performance significantly better with OTFC
Somnolence, nausea, constipation, and dizziness were the most common drug-associated AEs
Ashburn et al.,[11] 2011
180
FBT vs oral oxycodone; doubleblind, double-dummy, randomized, multiple crossover
PID 5, 10 and 15 min, SPID30 and SPID60 significantly greater after FBT. FBT was preferred
Adverse events with both study drugs were generally typical of opioids
Freye et al.,[12] 2007
76
EM vs oral morphine; open-label, compared with oral morphine in a preceding run-in period
Efficacy similar, mean time for PR significantly shorter with EM. Better satisfaction with EM
Similar AEs
Mercadante et al.,[13] 2007
25
IV morphine vs OTFC; open, randomized-controlled
Similar efficacy, short onset with IV AEs comparable morphine
Farrar et al.,[14] 1998
89
OTFC vs placebo; double-blind, randomized, multiple crossover
Better PR and less use of rescue medication with OTFC
Somnolence, nausea, constipation and dizziness were the most common drug-associated AEs
Portenoy et al.,[15] 1999
53
OTFC vs usual rescue drug; multicentre, randomized, double-blind, dose titration
Greater analgesic effect and more rapid onset at 15, 30 and 60 min than the usual rescue drug
Somnolence, nausea and dizziness. Very few adverse events were severe or serious
Christie et al.,[16] 1998
46
OTFC vs usual BTP medication; multicentre, randomized, double-blind, dose titration
OTFC produced a faster onset of relief and a greater degree of PR than patients’ usual breakthrough medication
Somnolence, nausea and dizziness were the most common AEs
Mercadante et al.,[17] 2009
86
OTFC vs INFS; randomized, open label, crossover
PID was statistically significantly greater for INFS than OTFC from 5 min post-dose. Higher SPID15 and SPID60 scores were achieved with INFS. More patients preferred INFS than OTFC and more patients found it very easy/easy to use
The only AE that occurred in ‡5% of patients in either treatment group was nausea. No serious AE
Portenoy et al.,[18] 2006
80
FBT vs placebo; double-blind, randomized, placebo-controlled
PR, PID, SPID, summed total PR, and patient ratings of global performance of medication significantly favoured FBT over placebo at all time points
Adverse events were typical of opioid drugs. Poor oral tolerability was noted in 2 patients
Slatkin et al.,[19] 2007
87
FBT vs placebo; randomized, double-blind, placebo-controlled
SPID60, PIDs and PR significantly favoured FBT vs placebo at 10 min and all subsequent time points
AEs were typical of opioids
Lennernas et al.,[20] 2010
27
SLF in different doses vs placebo; randomized, double-blind, crossover
Increase in PID, reduced use of rescue medication, improved global assessment with SLF 400 mg vs placebo
Nausea and dizziness were the most common treatment-related AEs
Rauck et al.,[21] 2009
61
SLF vs placebo; randomized, placebo-controlled
Improvements in SPID relative to placebo at 30 min and 60 min post-dose, PID and PR from 10 min post-dose
The observed pattern of AEs was consistent with that previously observed with fentanyl. One serious AE was considered possibly related to study medication
Kress et al.,[22] 2009
111
INFS vs placebo; randomized, placebo-controlled, crossover
PID10 with INFS was 2-fold that with placebo. Response rate with all 3 doses of INFS was 51.1% vs 20.9% with placebo
The prevalence of AEs was 22/111 (19.8%)
Continued next page
ª 2012 Adis Data Information BV. All rights reserved.
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Table II. Contd Study
Patients (n)
Design
Outcome
Portenoy et al.,[23] 2010
83
FPNS vs placebo; randomized, double-blind, crossover
FPNS improved SPID from 10 min Only 5.3% of patients withdrew until 60 min, improved PI scores as from treatment due to AEs early as 5 min, PID from 10 min, PR scores from 10 min, meaningful pain reduction from 10 min onward, reduced the use of rescue medication
Adverse effects
Davies et al.,[24] 2011
84
FPNS vs oral morphine; double-blind, double-dummy, multiple crossover
FPNS consistently provided better relief from 10 min, with differences in PI and percentages of episodes showing clinically meaningful pain relief. Acceptability scores were significantly greater for FPNS at 30 and 60 min
Only 4.7% of patients withdrew from titration because of AEs; no significant nasal effects were reported
Rauck et al.,[25] 2010
80
FBSF vs placebo; multicentre, randomized, double-blind, placebo-controlled, multiple crossover
SPID30 was greater for FBSFtreated episodes
There were no unexpected AEs
AEs = adverse effects; BTP = breakthrough pain; EM = effervescent morphine; FBSF = fentanyl buccal soluble film; FBT = fentanyl buccal tablet; FPNS = fentanyl pectin nasal spray; INFS = intranasal fentanyl spray; OTFC = oral transmucosal fentasnyl citrate; PI = pain intensity; PID = pain intensity difference, PR = pain relief; SLF = sublingual fentanyl; SPID = summed pain intensity differences; SPID30 = SPID at 30 minutes; SPID60 = SPID at 60 minutes.
data published in the literature are described in tables I and II, respectively. 3.4.1 Oral Transmucosal Fentanyl Citrate
OTFC is a fentanyl-impregnated lozenge, available in six dosage strengths (200, 400, 600, 800, 1200 and 1600 mg). Absolute availability is about 50%. However, the percentage absorbed by mouth and immediately available for treating BTP is about 25%, as the rest is swallowed.[26] Four early studies have shown the effectiveness of OTFC in the management of BTP. Patients receiving at least 60 mg of oral morphine or 50 mg/h of transdermal fentanyl were titrated with initial 200 mg to an effective dose of OTFC (maximum 1600 mg), and then randomly assigned to receive OTFC or placebo. OTFC produced significantly large changes in PI and better PR scores than placebo at all time points from 15 minutes to 60 minutes. Episodes treated with placebo required the use of rescue medication more often than episodes treated with OTFC. Adverse effects were those commonly associated with opioid therapy.[14] In a titration study, patients receiving 60–1000 mg of oral morphine equivalents were randomly treated with either 200 or 400 mg of OTFC in double-blind ª 2012 Adis Data Information BV. All rights reserved.
fashion and then titrated upward to an effective dose of OTFC (maximum 1600 mg). OTFC provided significantly greater analgesic effect at 15, 30 and 60 minutes, and a more rapid onset of effect than the usual rescue drug, presumably an oral opioid. Adverse effects of OTFC were those typically opioid related.[15] In another titration study, patients receiving transdermal fentanyl in doses of 50–300 mg/h were assigned to receive either 200 (for patients receiving
