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

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.

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

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.

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.

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.

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.

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

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

Breakthrough pain in children with cancer J Pain Symptom Manage Breakthrough pain in children with cancer J Pain Symptom Manage. 2007 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.

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.

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.

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.

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) www.nci.nih.gov/cancertopics/pdq/supportivecare/pain/HealthProfessional. 2Bennett et al. P&T 2005;30(6):354.

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

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.

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 30-60 minutes prior to activity Incident, predictable Lipophilic immediate-release opioid Incident, unpredictable Idiopathic Bennett et al. P&T. 2005;30(5):297

Current Medications for Breakthrough Pain

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

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.

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.

Opioids for the management of breakthrough (episodic) pain in cancer patients Cochrane Database Syst Rev Jan 2006 25;(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.

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.

* (*)

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.

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 60 mg morphine/day, 50 mcg transdermal fentanyl/hour, or equianalgesic dose of another opioid for a week or longer

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.

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 -10-15 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

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.

Analgetic Medications for Breakthrough pain in the Pipe Line

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 10 - 15 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. 2007 Dec;8(17):3043-51

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. 2007 Jul-Aug;5(7):327-34

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.

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 10-80 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.

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. 2007 Dec;7(4):324-31. Epub 2007 Nov 6.

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

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