Breakthrough Pain - Dolor Irruptivo.com

dolorirruptivo.com

Breakthrough Pain - Dolor Irruptivo.com

Breakthrough Pain

Russell Portenoy, MD

Chairman, Department of Pain Medicine and Palliative Care

Beth Israel Medical Center

New York, N.Y.

Professor of Neurology and Anesthesiology

Albert Einstein College of Medicine

Bronx, N.Y.


Breakthrough Pain

• Definitional issues

• Prevalence and impact

• Assessment issues

• Treatment issues


Breakthrough Pain:

Definitional Problems

• Justification for distinguishing a category of

pain

– Unique pathophysiology or etiology

– Clinical importance

– Treatment considerations

Breakthrough pain distinguished because of

empiric use of specific treatments, specifically

the so-called “rescue dose”, and evidence that it

is a clinically important phenomenon


Cancer-Related Breakthrough Pain:

Impact

• Compared with patients without breakthrough

pain, patients with breakthrough pain have

– More severe pain

– Reduced responsiveness to opioid therapy

Pain-related functional impairment

– Psychological distress

– Higher economic burden

Caraceni et al. Palliat Med. 2004;18:177-183.

Portenoy et al. Pain 1999; 81:129-134.

Fortner et al. Pain 2002;3:38-44.

Bruera et al. JPSM 1995;10:348-355.


Breakthrough Pain: Overall Pain

Control

100

80

60

40

20

0

93

55

Stage I Stages II and III

Patient Groups


Breakthrough Pain: Satisfaction with

Pain Control

Pain Control Satisfaction (%)

100

80

60

40

20

0

78

Patients without BTP Patients with BTP

25


Breakthrough Pain: Impact on

Mood

Mood VAS

80

70

60

50

40

30

20

10

0

75.1

60.2

Patients without BTP Patients with BTP


5

4

3

2

1

0

Function

4

2.7

3.6

2.5

3.5

2.3

3.9

2.5

2.9

1.9

Activity Mood Walk Work Social

Relations

Patients without BTP

Patients with BTP

Pain Interference Scale Breakthrough Pain: Impact on

3.2

2.2

3.7

2.7

Sleep Enjoy Life


Frequency (%)

Breakthrough Pain: Cost of Care

40%

30%

20%

10%

0%

Hospitalizations Estimated Annual Cost

36.9

22.5

Millions ($)

2.0

1.5

1.0

0.5

0.0

Patients with BTP (N=160)

Patients without BTP (N=89)

$ 1.7

Million

$192,000


Breakthrough Pain:

Definitional Problems

Breakthrough pain

– Definition is by consensus

and has arbitrary quality


Breakthrough Pain:

Definitional Problems

• Definitional problems related to use of alternative

terms

– Episodic pain

– Incident pain

– End-of-dose failure

Mercadante et al. Cancer, 2002; 94:832-839.

Svendsen et al. Cancer Surv, 2005; 9:195-206


Breakthrough Pain:

Definitional Problems

• Most studies use a version of:

– A transitory, severe or excruciating pain, which lasts

seconds to hours and is superimposed on a baseline

pain controlled to a moderate or better intensity by an

opioid regimen

• Most studies in the cancer population

– Explains opioid focus

Mercadante et al. Cancer, 2002; 94:832-839.

Svendsen et al. Cancer Surv, 2005; 9:195-206


Prevalence of Breakthrough Pain

• Cancer

– Community setting: 33%

– Inpatient settings: 50-90%

– Home care/inpatient hospice: 89%

• Non-cancer

– Primary care: 48%

– US pain clinics: 74%

Svendsen et al. Eur J Pain. 2005; 9:195-206.

Portenoy et al. Pain. 1999; 81:129-134.

Caraceni et al. Palliat Med. 2004;18:177-183.

Portenoy et al, JOM, in press


Breakthrough Pain: Characteristics

• Phenomenology usually similar to baseline pain, but

large inter-individual differences

• Frequency: < 1/day to many per hour

• Most episodes brief, but may last hours

• Onset usually over minutes, but varies

• 50% associated with voluntary action, but some nonvolitional

• May be predictable or appear without warning

Mercadante et al. Cancer. 2002; 94:832-839.

Caraceni et al. Palliative Med. 2004; 18:177-183.

Portenoy & Hagen. Pain. 1990; 4:273-281.


Cancer-Related

Breakthrough Pain: Predictability

Almost

always

11%

Often

7%

Always

15%

Sometimes

19%

Never

48%


Breakthrough Pain: Onset

• Cancer-related breakthrough pain (N=164)

– Time to peak intensity ranged from 1 second to 30

minutes

– Median 3.2 min

.


Breakthrough Pain: Treatment Issues

• Guidelines based on expert opinion

• Elements:

– Assessment

– Treatment of underlying etiology

– Optimizing regularly scheduled opioid

– Specific treatments for breakthrough pain

• Nonpharmacologic

• Pharmacologic

– Nonopioid

– Opioid

Portenoy and Hagen. Pain. 1990; Portenoy et al. Pain. 1999; 81:129-134.

Mercadante et al. Cancer. 2002; 94:832-839.


Breakthrough Pain: Treatment Issues

• Assessment Issues

– Characterize baseline pain and breakthrough pain

– Clarify syndrome, etiology and pathophysiology

– Determine relevant comorbidities and goals of care


Breakthrough Pain: Treatment Issues

• Treatment of underlying etiology

Pain etiology

• Example: RT to bone metastasis

– Precipitating events

• Examples:

– Antitussive for cough

– Limb orthotic for incident pain with movement


Breakthrough Pain: Treatment Issues

• Optimizing regularly scheduled opioid

– Viewed as most clearly useful for end-of-dose failure

– Theoretically helpful in reducing frequency or intensity

of other breakthrough pains

– Very few data


Breakthrough Pain: Treatment Issues

• Optimizing regularly scheduled opioid

– Open-label, short-term study of 25 advanced cancer

patients with movement-related episodic pain

• Opioid dose titrated above dose yielding pain relief at

rest to dose associated with limiting adverse effects

• Compared to admission

– Mean baseline pain on day 1 declined from 5.28 to 1.73

(p


Breakthrough Pain: Treatment Issues

• Specific treatments for breakthrough pain

– Nonpharmacologic

– Pharmacologic


Breakthrough Pain: Treatment Issues

• Nonpharmacologic treatments for breakthrough

pain

– Application of heat or cold

– Massage or stretching

– Cognitive technique like deep relaxation, mental

imagery or self-hypnosis


Breakthrough Pain: Treatment Issues

• Pharmacologic treatments for breakthrough pain

– Nonopioid

• Example: NSAID

• Example: nasal or sublingual ketamine

• Example: spinal local anesthetic

– Opioid

Carr et al. Pain. 2004;108:17-27

Mercadante et al. JPSM; 2005;30:285-291


Treatment of BTP using Intranasal

Ketamine

Numerical Pain Intensity Scale

Change from Baseline

0

-1

-2

-3

-4

-5

0

Dosing

Period

*

* *

* * *

10 20 30 40 50 60

Time, min

*

*

Placebo

Ketamine

N=20


Breakthrough Pain: Opioid Treatment

• Opioid treatment for breakthrough pain

– Known as “rescue dose”

– Standard of care for cancer patients receiving a baseline

opioid regimen for chronic pain

– Used variable in the noncancer chronic pain

populations

– Treatment guidelines based on expert opinion

– Limited data and many unknowns


“Rescue Dose” According to Expert

Opinion

• Expert opinion:

– Drug should be identical to fixed scheduled opioid but

formulation should have a short half-life, a rapid onset

and short duration of effect

– Drug should be given by the same route as the fixed

scheduled opioid

– Drug should be given at a dose that is a fixed

proportion of the baseline dose

– Rescue dose should be titrated over time just like the

baseline opioid regimen

Jacox A, Carr DB, Payne R, et al. Management of Cancer Pain. Clinical Practice Guideline No. 9., 1994.

American Pain Society. Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain, 2003.

Mercadante et al. Cancer. 2002; 94:832-839.


“Rescue Dose” According to Expert

Opinion

• Expert opinion:

– Very little supporting data for recommendations

– Advent of rapid onset formulations have questioned some

assumptions

• Same drug?

• Same route?

• Proportionate dose?

– New question: When should rapid onset opioids be used


“Rescue Dose”

• Most common approach at the present time

– Oral or IV/SQ rescue doses

• Same drug and route as baseline

• “PRN” dose at 5-15% of the total daily dose

• Offered every 1-2 hours if oral and every 15-60 minutes

if IV/SQ

• Dose titration is often necessary


“Rescue Dose”

• Study of fixed proportion “rescue dose”

– Open-label, short-term study of 48 advanced cancer

patients with episodic pain receiving oral opioid

regimens

• IV morphine given at 20% of total daily dose for

episodes of pain

– In 136/171 (80%) episodes, >50% pain relief in mean 16.6

minutes

– In 162/171 (95%), >33% pain relief in mean 17.7 minutes

– Adverse events uncommon and tolerable

Mercadante et al. JPSM. 2004; 27:352-359.


“Rescue Dose”

• Studies of fixed proportion “rescue dose”

– Controlled trials of oral transmucosal fentanyl citrate

and fentanyl effervescent buccal tablet showed no

relationship between size of rescue dose and baseline

opioid regimen

– Conclusion: Titration from low initial dose is needed

for rapid onset fentanyl formulations

Lichtor et al. Anesthesia and Analgesia.1999; 88:732-738.

Portenoy et al. Pain.1999; 81:129-134.

Portenoy R, et al. Presented at the AAPM meeting, 2006.


“Rescue Dose”

• Study of methadone “rescue dose”

– Open-label, short-term, crossover study of methadone

vs. usual “rescue dose” in 6 patients with cancer pain

• In 37 episodes, onset of analgesic effect was rapid; 3 patients

experienced onset by 10 minutes

• Adverse effect profile of oral methadone was same as usual

drug

• Patients were moderately to completely satisfied

– Conclusion: Use of a long half-life drug may be acceptable

in some patients

Fisher et al. JPSM. 2004; 28:619-625.


“Rescue Dose”

• New rapid onset formulations

– Mismatch between phenomenology and time-action

of oral drug suggested opportunity for better

outcomes with rapid onset formulations

– Rapid onset opioids use lipophilic drug and transmucosal

route to approach the time-action of an IV bolus


Pain Intensity

Rapid Onset Opioids: Addressing

the Mismatch

Rescue Dose

Baseline Pain

Time

Around-The-Clock

Medication

Fentanyl

(ng/mL ± SEM)

400 µg I.V.

400 µg FEBT

800 µg OTFC

800 µg Oral

2.5

2.0

1.5

1.0

0.5

0.0

1.0

0.5

0.0

0 1

0 1 2 3 4 5 6

Time, h


Rapid-Onset “Rescue Dose”

• Approved formulations in the US and Europe

– Oral transmucosal fentanyl citrate

– Fentanyl effervescent buccal tablet

– Bio-erodible mucoadhesive (BEMA ) patch

– Fentanyl solution nasal spray

– Sublingual fentanyl tablet


Oral Transmucosal Fentanyl Citrate

(OTFC)

• First rapid onset formulation

• Demonstrated viability of using fentanyl

• Median onset of relief = 5 minutes; peak plasma

concentration +/- 22 minutes

• Clinical trials demonstrate safety and efficacy

• Limited comparative data

Lichtor et al. Anesthesia and Analgesia.1999; 88:732-738. Streisand et al. Anesthesiology.

1991; 75:223-231.Portenoy et al. Pain.1999; 81:129-134. Payne et al. J Pain Symptom Mange.

2001; 22:575-583.


Study

OTFC in Breakthrough Cancer Pain

Pain Intensity at 15 Minutes

Christie 1998

Coluzzi 2001

Farrar 1998

Portenoy 1999 a

Total (95% CI)

Weighted Mean Difference (Fixed) 95% CI

-4.0 -2.0 0 2.0 4.0

Favors OTFC Favors Control


Rapid Onset “Rescue Dose” vs. Oral

Morphine: Study of OTFC

• Controlled comparative trial

– Double-blind, double-dummy, randomized, multiple

crossover study in 134 ca patients with BTP

– Compared 'successful' MSIR dose (15-60 mg) and

optimally titrated OTFC

– 69% of patients (93/134) found a successful dose of

OTFC

– OTFC yielded better pain relief than MSIR at all time

points that were significantly better than MSIR

Coluzzi et al. Pain. 2001;91:123-130.


Fentanyl

(ng/mL ± SEM)

Rapid Onset Formulations: Trying to

Approach the IV Bolus

2.5

2.0

1.5

1.0

0.5

0.0

400 µg I.V.

400 µg FEBT

800 µg OTFC

800 µg Oral

0 1 2 3 4 5 6

1.0

0.5

0.0

Time, h

0 1


% of Episodes with

> 33% Improvement

FEBT: Placebo-Controlled Trial

80

70

60

50

40

30

20

10

0

14

9

49

29

15 min 30 min 45 min 60 min

Time (min)

71

44

75

48

FEBT

Placebo

P < 0.05 at all time

points


Episodes, %

RCT of Fentany Pectin Nasal Spray:

% Episodes w/ =1-Point Pain Reduction

100

90

80

70

60

50

40

30

20

10

0

33.3

*

26.5

61

**

44

73.2

5 10 15 30 45 60

*P=0.04 vs placebo.

**P


Formulations in Development

• Fentanyl pectin nasal spray

• Aerosolized fentanyl formulations

• Micro-needle systems

• Morphine-chitosan nasal spray formulation

• Hydromorphone nasal spray formulation

• Fentanyl sublingual spray

• Iontophoretic PCA patch

• Sublingual or intranasal sufentanil


Rapid Onset Opioids: Concerns

• Most of the use in the US is off-label

• Unintentional overdose probably related to

unsophisticated prescribers, wrong patient population

• Separate concern about drug abuse issues

– Attractiveness to those with addiction, leading to

diversion

– Likelihood of relapse or iatrogenic addiction

• Voluntary REMS programs in the US pre-empting

mandatory REMS


Opioid Treatment of Breakthrough Pain:

Unresolved Issues

• Conclusions

– A consensus-driven treatment strategy may be helpful:

• Assessment

• Treating pain etiology or precipitating events

• Optimizing baseline analgesic regimen, and

• Using symptomatic pharmacologic and non-pharmacologic

therapies

– Use of “rescue doses” has become conventional practice for

cancer-related breakthrough pain and appears to be useful

– Role of rapid onset formulations is evolving


Opioid Treatment of Breakthrough Pain:

Unresolved Issues

• Still many unknowns

– What is the “best” definition for breakthrough pain

– Does the effective treatment of breakthrough pain reduce all

the associated adverse events and consequences


Opioid Treatment of Breakthrough Pain:

Unresolved Issues

• Still many unknowns

– When using opioids to treat breakthrough pain

• Is dosing proportional to baseline dose necessary or best

approach?

• Would use of a drug different than baseline drug improve

efficacy?

• Do rapid onset drugs yield added benefit?

• Do the rapid onset drugs pose added risk?

• How should nonopioid and nonpharmacological approaches be

combined with drug therapy?

More magazines by this user
Similar magazines