Breakthrough Pain An Update

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Breakthrough Pain An Update

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

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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 199041273. 2Coluzzi. Am
J Hosp Palliat Care 19981513. 3Hanks et al.
Oxford Textbook of Palliative Medicine 1998454.
4Bennett et al. PT 200530(5)296.
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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. PT. 200530(6)354
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Prevalence

• In cancer patients
• At diagnosis 30 to 40
• During active treatment 50 to 70
• During endstage disease 70 to 801
• International study data (n1095) 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 20059(2)195.
2Caraceni Portenoy. Pain 199982263.
3Zeppetella et al. Palliat Med 200115243.
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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.

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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 20053(1)38. 2Grant et
al. Nurs Clin North Am. 199530(4)674. 3Fortner
et al. J Pain Symptom Manage 200325(1)9.
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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. PT 200530(5)296. 2Svendsen et
al. Eur J Pain 20059(2)195.
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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. PT. 200530(5)296
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Treating cancer-related breakthrough pain the
oral transmucosal routeInt J Palliat Nurs 2007
Jul13(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

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Breakthrough pain in children with cancerJ Pain
Symptom Manage. 2007 Aug34(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.

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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.

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Subtypes of BTP

• Incident (50 of BTP episodes)
• 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 (gt30 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. PT 200530(5)296.
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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. PT 200530(6)354.
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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. PT 200530(6)354.
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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

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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. PT 200530(6)354.
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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
Lipophilic immediate-release opioid Idiopathic
Bennett et al. PT. 200530(5)297
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Current Medications for Breakthrough Pain
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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. PT. 200530(6)354
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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. PT. 200530(6)354 Lynch. Pain
Res Manag. 200510(3)133.
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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 200191123 2
FarrarThompson. APS annual meeting 2005
3Shalova et al. J Nati Med Assoc. 200496984.
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Opioids for the management of breakthrough
(episodic) pain in cancer patientsCochrane
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.

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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.

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()
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Absorption of Opioids from Oral Mucosa
Commonly prescribed opioid medications
Mean Absorbed
Heroin (2.5)
Fentanyl (0.5)
Naloxone (1.0)
Oxycodone (2.5)
Methadone (5.0)
Methadone (0.8)
Levorphanol (1.0)
Buprenorphene (0.1)
Hydromorphone (1.0)
Morphine (5.0)
Opioid (dose in mg)
Adapted from Weinberg DS, et al. Clin Pharm Ther.
198844337.
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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

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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.
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Summary IR Opioids for BTP
Characteristics of Immediate-Release Opioid
Useful for Breakthrough Pain (BTP)
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 4 hrs 30 min Oxycodone (oral)
D- no liquid concentrate, slow onset of analgesic for Idiopathic BTP 4 hrs 30 min 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)
Hydrophilic
Lipophilic
Bennett et al. PT. 200530(6)354
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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. 200559249.
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Analgetic Medications for Breakthrough pain in
the Pipe Line
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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 Dec8(17)3043-51

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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-Aug5(7)327-34

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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.

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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
  lt 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 lt
  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.

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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 Dec7(4)324-31. Epub 2007 Nov
  6.

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A trial looking at fentanyl nasal spray to treat
breakthrough cancer painCancer 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 01/05/2007Ends 01/06/2008
• Phase 3
• Miranda PenhaligonArchimedes Pharmaceuticals

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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