1. Breakthrough Pain An Update
Prof. Pesach Shvartzman
Pain and Palliative Care Unit,
Ben-Gurion University of the Negev,
Clalit Health Services,
Beer-Sheva, Israel

2. Definitions for BTP
A transient increase in pain to greater than moderate intensity, occurring on a baseline pain of moderate intensity or less.
Historic Definition1
A transitory flare of pain superimposed on an otherwise stable pain pattern in patients treated with opioids.
Narrow Definition2
Any acute transient pain the flares over baseline.
Broad Definition3
A transient exacerbation of pain occurring in patients with otherwise stable, baseline persistent pain.
Consensus Panel Recommendation4
1Portenoy & Hagen. Pain 1990;41:273. 2Coluzzi. Am J Hosp Palliat Care 1998;15:13. 3Hanks et al. Oxford Textbook of Palliative Medicine 1998;454. 4Bennett et al. P&T 2005;30(5):296.

4. Epidemiology 19% to 95% of patients with pain also experience BTP
The wide range reflects both the type of patient population sampled, and the definition of BTP used
Bennett et al. P&T. 2005;30(6):354

5. Prevalence In cancer patients:
At diagnosis: 30% to 40%
During active treatment: 50% to 70%
During endstage disease: 70% to 80%1
International study data (n=1095) indicate that around two thirds of cancer patients experience BTP2.
In non-cancer patients:
Of 43 terminally-ill hospice patients with pain, 27 reported BTP3.
1Svendsen et al. Eur J Pain 2005;9(2):195. 2Caraceni & Portenoy. Pain 1999;82:263. 3Zeppetella et al. Palliat Med 2001;15:243.

6. Personal Burden of Disease
BTP has an overall demoralizing effect on patients and their families.
It is strongly associated with:
Impaired daily functioning
Worsening of depression and anxiety
Dissatisfaction with opioid therapy
Poor medical outcomes.

7. Socioeconomic Burden of Disease
Patients with BTP are also likely to utilize more healthcare resources than patients without BTP1
More pain-related hospitalization1,2
More pain-related emergency department visits2
Increased direct and indirect treatment costs3
1Fortner et al. J Pain 2005;3(1):38. 2Grant et al. Nurs Clin North Am. 1995;30(4):674. 3Fortner et al. J Pain Symptom Manage 2003;25(1):9.

8. Features of BTP
The cause and anatomical site of BTP is often, but not always, the same as that of the chronic baseline pain.
Clinical features of BTP are similar among patients with and without malignant disease.
1Bennett et al. P&T 2005;30(5):296. 2Svendsen et al. Eur J Pain 2005;9(2):195.

9. BTP Episodes
In some patients, several episodes of BTP may occur on a daily basis.
More than 4 episode per day may warrant reassessment of the cause and approach for management of baseline chronic pain.
Bennett et al. P&T. 2005;30(5):296

10. Treating cancer-related breakthrough pain: the oral transmucosal route Int J Palliat Nurs 2007 Jul;13(7):326-31
Between 40 and 80% of patients with advanced cancer experience breakthrough pain (BTP)
. Patients often have up to four episodes of BTP each day
A typical episode reaching its peak intensity in three to five minutes and lasting about 30 minutes in total.
It is essential to provide fast relief.
BTP reduces the quality of life of patients and their families, and increases health care costs.
The usual approach is to treat BTP with a short-acting opioids
Oral transmucosal fentanyl citrate (Actiq) is an effective strong opioid that has a rapid onset and short duration of action

11. Breakthrough pain in children with cancer J Pain Symptom Manage
Breakthrough pain in children with cancer J Pain Symptom Manage Aug;34(2):209-16
A prospective study to determine the prevalence, characteristics, and impact of breakthrough pain in children with cancer.
Twenty-seven pediatric inpatients with cancer (aged 7-18 years) who had severe pain requiring treatment with opioids
Structured interview.
Measures of pain, anxiety, and depressed mood were completed.

12. Results
Fifty-seven percent of the children experienced one or more episodes of breakthrough pain during the preceding 24 hours, each episode lasting seconds to minutes, occurring 3-4 times/d, and most commonly characterized as "sharp" and "shooting" by the children.
Younger children (7-12 years) had a significantly higher risk
The most effective treatment was a patient-controlled analgesia opioid bolus dose.

13. Subtypes of BTP Incident (~50% of BTP episodes) Idiopathic End of dose
Predictable: consistent, strong, temporal relationship with a precipitating factor (eg, movement).
Unpredictable: inconsistent temporal realtionship with motor activity (eg, bladder spasm).
Idiopathic
Not induced by a readily identifiable cause.
Lasts longer than incident pain (>30 minutes).
End of dose
Presents prior to a scheduled dose of an around-the-clock analgesic.
Gradual in onset and of longer duration than both incident and idiopathic pain.
Bennett et al. P&T 2005:30(5):296.

14. Treatment Options
The appropriate intervention is determined by the type, severity and pattern of BTP
Attempt to find a correctable cause of BTP that may be reversed
Radiation or strontium (89SR) chloride therapy for palliation of bone secondaries
Surgical debulking of solid tumors
Vertebroplasty for hitherto undiagnosed compression fracture
Then consider pharmacologic and nonpharmacologic (physical and psychosocial) therapies.
Bennett et al. P&T 2005:30(6):354.

15. Nonpharmacologic Intervention
Lifestyle interventions
Self-awareness of physical limitations
Pace activities with regular breaks
Use of ice packs, massage, exercise, repositioning, and immobilization to remove focus from pain sensation.
Healthcare system interventions
Transcutaneous electrical nerve stimulation (TENS) and acupuncture
Cognitive-behavioral techniques (hypnosis, relaxation methods)2
1NCI. Pain (PDQ) 2Bennett et al. P&T 2005;30(6):354.

16. Ideal BTP Medication Potent pain reliever Rapid onset of action
Sufficient duration of effect to treat BTP episode
Minimal or manageable side effects
Easy to administer

17. Pharmacologic Intervention
Goal: reduce the frequency and intensity of BTP
If BTP regularly occurs at the end of each scheduled dosing interval, then two options are available:
Increase total daily dose of opioid by 25-50%.
Shorten the dosage interval
Approximately one sixth of the total daily analgesic dose is given as an immediate release preparation to control BTP
Bennett et al. P&T 2005:30(6):354.

18. Management by subtype of Breakthrough Pain
General Management Approach
Subtype
Carefully tailor around-the-clock dosing
End-of-dose
Pre-emptive immediate-release opioid, given minutes prior to activity
Incident, predictable
Lipophilic immediate-release opioid
Incident, unpredictable
Idiopathic
Bennett et al. P&T. 2005;30(5):297

21. Current Medications for Breakthrough Pain

22. Oral Immediate-release (IR) opioids for BTP
Hydrocodone, morphine, oxycodone, hydromorphone, combination with paracetamol/aspirin
Oral absorption means slower onset analgesia (+/- 30 min)
Duration of effect +/- 4hrs
Useful for predictable incident pain
Less suitable for severe idiopathic or unpredictable incident BTP
Bennett et al. P&T. 2005;30(6):354

23. Oral IR Opioids for BTP: Methadone
Rapid onset (10-15 min), excellent oral and rectal absorption
Opioid agonist, NMDA antagonism, and monoaminergic effects
Duration of effect (4-6 hours)
Accumulation, toxicity possible with frequents dosing
Bennett et al. P&T. 2005;30(6):354; Lynch. Pain Res Manag. 2005;10(3):133.

24. Opioid Efficacy Studies in BTP
Oral transmucosal fentanyl citrate (OTFC)
More effective than IR oral morphine for cancer-related BTP pain1
Effective for neuropathic, nonciceptive BTP2
Effective in outpatients with sickle-cell pain3
1 Coluzzi et al. Pain 2001;91:123; 2 Farrar&Thompson. APS annual meeting 2005; 3Shalova et al. J Nati Med Assoc. 2004;96:984.

25. Opioids for the management of breakthrough (episodic) pain in cancer patients Cochrane Database Syst Rev Jan ;(1)
Four studies (393 participants) met the inclusion criteria
All were concerned with the use of oral transmucosal fentanyl citrate (OTFC) in the management of breakthrough pain.
Two studies examined the titration of OTFC, one study compared OTFC to normal release morphine and one study compared OTFC to placebo.OTFC was shown to be an effective treatment for breakthrough pain.

26. Cochrane Database Syst Rev Jan 2006 25;(1)
When compared to placebo and morphine, participants gave lower pain intensity scores and higher pain relief scores for OTFC at all time points. Global assessment scores also favoured OTFC.
There is evidence that OTFC is an effective treatment in the management of breakthrough pain.
The randomised trial literature for the management of breakthrough pain is small and no trials were found for other opioids.

27. *
(*)

28. Absorption of Opioids from Oral Mucosa
Commonly prescribed opioid medications 10 20 30 40 50 60 70 80
Mean % Absorbed
Fentanyl was chosen for administration via the oral transmucosal route because it is very potent and readily absorbed from the oral cavity. Under conditions of controlled pH and minimal swallowing, sublingual absorption of 1 mL aliquots of various opioids was recorded in healthy volunteers over a 10-minute period, with 10 to 35 volunteers receiving each test drug.13 Drugs tested included morphine sulfate, oxycodone, levorphanol, hydromorphone, naloxone, methadone (2 concentrations), heroin, fentanyl, and buprenorphine. Overall, lipophilic drugs were better absorbed than hydrophilic drugs. Morphine was only 18% bioavailable. Methadone (34% absorbed), fentanyl (51%), and buprenorphine (55%) were absorbed to a significantly greater degree than morphine. Buprenorphine is only a partial mu-agonist and is not a good choice as a step 2 opioid. It also exhibits a depot effect when administered sublingually, and it has a prolonged duration of action. The pharmacokinetics of methadone (long plasma half-life) preclude its use as a breakthrough pain medication.
Heroin (2.5)
Naloxone (1.0)
Fentanyl (0.5)
Oxycodone (2.5)
Levorphanol (1.0)
Methadone (5.0)
Methadone (0.8)
Morphine (5.0)
Hydromorphone (1.0)
Buprenorphene (0.1)
Opioid (dose in mg)
Adapted from Weinberg DS, et al. Clin Pharm Ther. 1988;44:337.

29. ACTIQ Indication ACTIQ was FDA approved in April, 1999
ACTIQ is indicated in the US for the management of breakthrough cancer pain in patients with malignancies who are already receiving and who are tolerant* to opioid therapy for their underlying persistent cancer pain.
* Patients considered opioid tolerant are those who are taking at least mg morphine/day, 50 mcg transdermal fentanyl/hour, or equianalgesic dose of another opioid for a week or longer

30. Pharmacodynamics – Onset of Pain Relief
Once in the bloodstream, fentanyl is rapidly distributed to the CNS (a process with a 3- to 5-minute half-life)
Onset of pain relief may begin while consuming an ACTIQ unit (within 15 minutes)
Full pain relief may not be felt for up to 45 minutes after consuming an ACTIQ unit
Longer or shorter consumption times may produce less efficacy than reported in ACTIQ clinical trials
ACTIQ Package Insert. May 2003.

31. Summary: IR Opioids for BTP
Characteristics of Immediate-Release Opioid Useful for Breakthrough Pain (BTP)
Hydrophilic
Advantages (A)/ Disadvantages (D)
Duration of Effect
Onset of Analgesia
Immediate-Release Opioid
A- available in multiple dosage forms, liquid concentrate
D- slow onset of analgesia for Idiopathic BTP
4 hrs
30-40 min
Morphine (oral)
Same as morphine
30 min
Oxycodone (oral)
D- no liquid concentrate, slow onset of analgesic for Idiopathic BTP
Hydromorphone (oral)
A- faster onset of analgesic in one small study
D- complex pharmacology, pharmacokinetics
4-6 hrs
min
Methadone (oral)
A- fastest onset of analgesia
D- requires ongoing patient cooperation in use
1-2 hrs
-5-10 min
Fentanyl
(trans-mucosal)
Lipophilic
Bennett et al. P&T. 2005;30(6):354

32. Investigational Opioid for BTP
Sublingual fentanyl
Dissolves rapidly
Detectable plasma levels in8-11 minutes
Well-tolerated in patients with metastatic cancer
Lennernds et al. Br J Pharmacol. 2005;59:249.

33. Analgetic Medications for Breakthrough pain in the Pipe Line

34. Fentanyl Buccal Tablet:
New sugar-free, that uses an effervescent drug delivery system to enhance the rate and extent of fentanyl absorption across the buccal mucosa.
Pain relief is observed within min of administration.
Generally well tolerated, with the most commonly observed adverse events being typical opioid side effects.
Represent a convenient and effective treatment for the control of breakthrough pain.
Expert Opin Pharmacother Dec;8(17):

35. Fentanyl buccal tablet for relief of breakthrough pain in opioid-tolerant patients with cancer-related chronic pain .
In this study of opioid-tolerant patients with chronic cancer pain and BTP, FBT was efficacious, well tolerated, demonstrated rapid onset of analgesia (within 10 minutes), and had a sustained effect.
J Support Oncol Jul-Aug;5(7):327-34

36. Effervescent morphine results in faster relief of breakthrough pain in patients compared to immediate release morphine sulfate tablet
Effervescent morphine was given to 76 chronic cancer pain patients for treatment of BTP evaluating time until pain relief, global satisfaction and side effects. Results were compared to those obtained using an IRMS formulation in a preceding run-in period.

37. Effervescent morphine results in faster relief of breakthrough pain in patients compared to immediate release morphine sulfate tablet
A mean dose of 28 mg of effervescent morphine (range mg) resulted in a highly significant reduction of pain score (mean 7.8 to mean 3.2; P < 0.001).
Efficacy was not different from that observed with IRMS. However, mean time until sufficient pain relief was significantly shorter than with IRMS (13 +/- 5.6 vs. 27 +/- 4.4 minutes; P < 0.01).
The incidence of side effects was similar with the new morphine formulation and with IRMS.
There was no relationship between the previous dose of the daily opioid and the effective dose of effervescent morphine.

38. Effervescent morphine results in faster relief of breakthrough pain in patients compared to immediate release morphine sulfate tablet
Overall satisfaction for effervescent morphine was rated "superior" by 16.7%, and "better" by 63.2% of patients.
Pain Pract Dec;7(4): Epub 2007 Nov 6.

39. A trial looking at fentanyl nasal spray to treat breakthrough cancer pain Cancer Research UK
This trial will compare fentanyl citrate nasal spray (also called NasalFent) with other painkillers that are already used to treat cancer pain.
Starts 01/05/2007 Ends 01/06/2008
Phase 3
Miranda Penhaligon Archimedes Pharmaceuticals

40. Conclusion
BTP is a common, disabling feature of malignant disease and other illnesses
There are 3 subtypes of BTP (incident, idiopathic, and end-of-dose)
BTP is assessed and managed separately from chronic baseline pain
Consider pharmacologic and non- pharmacologic utilities
Appropriate assessment , planning, and patient education can reduce the frequency and severity of BTP in most patients