Presentation on theme: "Breakthrough Pain An Update"— Presentation transcript:
1 Breakthrough Pain An Update Prof. Pesach ShvartzmanPain and Palliative Care Unit,Ben-Gurion University of the Negev,Clalit Health Services,Beer-Sheva, Israel
2 Definitions for BTPA transient increase in pain to greater than moderate intensity, occurring on a baseline pain of moderate intensity or less.Historic Definition1A transitory flare of pain superimposed on an otherwise stable pain pattern in patients treated with opioids.Narrow Definition2Any acute transient pain the flares over baseline.Broad Definition3A transient exacerbation of pain occurring in patients with otherwise stable, baseline persistent pain.Consensus Panel Recommendation41Portenoy & 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 usedBennett 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%1International 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 functioningWorsening of depression and anxietyDissatisfaction with opioid therapyPoor medical outcomes.
7 Socioeconomic Burden of Disease Patients with BTP are also likely to utilize more healthcare resources than patients without BTP1More pain-related hospitalization1,2More pain-related emergency department visits2Increased direct and indirect treatment costs31Fortner 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 BTPThe 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 EpisodesIn 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):326-31Between 40 and 80% of patients with advanced cancer experience breakthrough pain (BTP). Patients often have up to four episodes of BTP each dayA 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 opioidsOral 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):209-16A 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 opioidsStructured interview.Measures of pain, anxiety, and depressed mood were completed.
12 ResultsFifty-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 riskThe 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).IdiopathicNot induced by a readily identifiable cause.Lasts longer than incident pain (>30 minutes).End of dosePresents 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 OptionsThe appropriate intervention is determined by the type, severity and pattern of BTPAttempt to find a correctable cause of BTP that may be reversedRadiation or strontium (89SR) chloride therapy for palliation of bone secondariesSurgical debulking of solid tumorsVertebroplasty for hitherto undiagnosed compression fractureThen consider pharmacologic and nonpharmacologic (physical and psychosocial) therapies.Bennett et al. P&T 2005:30(6):354.
15 Nonpharmacologic Intervention Lifestyle interventionsSelf-awareness of physical limitationsPace activities with regular breaksUse of ice packs, massage, exercise, repositioning, and immobilization to remove focus from pain sensation.Healthcare system interventionsTranscutaneous electrical nerve stimulation (TENS) and acupunctureCognitive-behavioral techniques (hypnosis, relaxation methods)21NCI. 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 episodeMinimal or manageable side effectsEasy to administer
17 Pharmacologic Intervention Goal: reduce the frequency and intensity of BTPIf 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 intervalApproximately one sixth of the total daily analgesic dose is given as an immediate release preparation to control BTPBennett et al. P&T 2005:30(6):354.
18 Management by subtype of Breakthrough Pain General Management ApproachSubtypeCarefully tailor around-the-clock dosingEnd-of-dosePre-emptive immediate-release opioid, given minutes prior to activityIncident, predictableLipophilic immediate-release opioidIncident, unpredictableIdiopathicBennett et al. P&T. 2005;30(5):297
22 Oral Immediate-release (IR) opioids for BTP Hydrocodone, morphine, oxycodone, hydromorphone, combination with paracetamol/aspirinOral absorption means slower onset analgesia (+/- 30 min)Duration of effect +/- 4hrsUseful for predictable incident painLess suitable for severe idiopathic or unpredictable incident BTPBennett et al. P&T. 2005;30(6):354
23 Oral IR Opioids for BTP: Methadone Rapid onset (10-15 min), excellent oral and rectal absorptionOpioid agonist, NMDA antagonism, and monoaminergic effectsDuration of effect (4-6 hours)Accumulation, toxicity possible with frequents dosingBennett 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 pain1Effective for neuropathic, nonciceptive BTP2Effective in outpatients with sickle-cell pain31 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 criteriaAll 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.
28 Absorption of Opioids from Oral Mucosa Commonly prescribed opioid medications1020304050607080Mean % AbsorbedFentanyl 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 unitLonger or shorter consumption times may produce less efficacy than reported in ACTIQ clinical trialsACTIQ Package Insert. May 2003.
31 Summary: IR Opioids for BTP Characteristics of Immediate-Release Opioid Useful for Breakthrough Pain (BTP)HydrophilicAdvantages (A)/ Disadvantages (D)Duration of EffectOnset of AnalgesiaImmediate-Release OpioidA- available in multiple dosage forms, liquid concentrateD- slow onset of analgesia for Idiopathic BTP4 hrs30-40 minMorphine (oral)Same as morphine30 minOxycodone (oral)D- no liquid concentrate, slow onset of analgesic for Idiopathic BTPHydromorphone (oral)A- faster onset of analgesic in one small studyD- complex pharmacology, pharmacokinetics4-6 hrsminMethadone (oral)A- fastest onset of analgesiaD- requires ongoing patient cooperation in use1-2 hrs-5-10 minFentanyl(trans-mucosal)LipophilicBennett et al. P&T. 2005;30(6):354
32 Investigational Opioid for BTP Sublingual fentanylDissolves rapidlyDetectable plasma levels in8-11 minutesWell-tolerated in patients with metastatic cancerLennernds 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 tabletEffervescent 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 tabletA 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 tabletOverall 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 01/06/2008Phase 3Miranda Penhaligon Archimedes Pharmaceuticals
40 ConclusionBTP is a common, disabling feature of malignant disease and other illnessesThere are 3 subtypes of BTP (incident, idiopathic, and end-of-dose)BTP is assessed and managed separately from chronic baseline painConsider pharmacologic and non- pharmacologic utilitiesAppropriate assessment , planning, and patient education can reduce the frequency and severity of BTP in most patients