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<strong>Breakthrough</strong> <strong>Pain</strong><br />

Russell Portenoy, MD<br />

Chairman, Department of <strong>Pain</strong> Medicine and Palliative Care<br />

Beth Israel Medical Center<br />

New York, N.Y.<br />

Professor of Neurology and Anesthesiology<br />

Albert Einstein College of Medicine<br />

Bronx, N.Y.


<strong>Breakthrough</strong> <strong>Pain</strong><br />

• Definitional issues<br />

• Prevalence and impact<br />

• Assessment issues<br />

• Treatment issues


<strong>Breakthrough</strong> <strong>Pain</strong>:<br />

Definitional Problems<br />

• Justification for distinguishing a category of<br />

pain<br />

– Unique pathophysiology or etiology<br />

– Clinical importance<br />

– Treatment considerations<br />

• <strong>Breakthrough</strong> pain distinguished because of<br />

empiric use of specific treatments, specifically<br />

the so-called “rescue dose”, and evidence that it<br />

is a clinically important phenomenon


Cancer-Related <strong>Breakthrough</strong> <strong>Pain</strong>:<br />

Impact<br />

• Compared with patients without breakthrough<br />

pain, patients with breakthrough pain have<br />

– More severe pain<br />

– Reduced responsiveness to opioid therapy<br />

– <strong>Pain</strong>-related functional impairment<br />

– Psychological distress<br />

– Higher economic burden<br />

Caraceni et al. Palliat Med. 2004;18:177-183.<br />

Portenoy et al. <strong>Pain</strong> 1999; 81:129-134.<br />

Fortner et al. <strong>Pain</strong> 2002;3:38-44.<br />

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


<strong>Breakthrough</strong> <strong>Pain</strong>: Overall <strong>Pain</strong><br />

Control<br />

100<br />

80<br />

60<br />

40<br />

20<br />

0<br />

93<br />

55<br />

Stage I Stages II and III<br />

Patient Groups


<strong>Breakthrough</strong> <strong>Pain</strong>: Satisfaction with<br />

<strong>Pain</strong> Control<br />

<strong>Pain</strong> Control Satisfaction (%)<br />

100<br />

80<br />

60<br />

40<br />

20<br />

0<br />

78<br />

Patients without BTP Patients with BTP<br />

25


<strong>Breakthrough</strong> <strong>Pain</strong>: Impact on<br />

Mood<br />

Mood VAS<br />

80<br />

70<br />

60<br />

50<br />

40<br />

30<br />

20<br />

10<br />

0<br />

75.1<br />

60.2<br />

Patients without BTP Patients with BTP


5<br />

4<br />

3<br />

2<br />

1<br />

0<br />

Function<br />

4<br />

2.7<br />

3.6<br />

2.5<br />

3.5<br />

2.3<br />

3.9<br />

2.5<br />

2.9<br />

1.9<br />

Activity Mood Walk Work Social<br />

Relations<br />

Patients without BTP<br />

Patients with BTP<br />

<strong>Pain</strong> Interference Scale <strong>Breakthrough</strong> <strong>Pain</strong>: Impact on<br />

3.2<br />

2.2<br />

3.7<br />

2.7<br />

Sleep Enjoy Life


Frequency (%)<br />

<strong>Breakthrough</strong> <strong>Pain</strong>: Cost of Care<br />

40%<br />

30%<br />

20%<br />

10%<br />

0%<br />

Hospitalizations Estimated Annual Cost<br />

36.9<br />

22.5<br />

Millions ($)<br />

2.0<br />

1.5<br />

1.0<br />

0.5<br />

0.0<br />

Patients with BTP (N=160)<br />

Patients without BTP (N=89)<br />

$ 1.7<br />

Million<br />

$192,000


<strong>Breakthrough</strong> <strong>Pain</strong>:<br />

Definitional Problems<br />

• <strong>Breakthrough</strong> pain<br />

– Definition is by consensus<br />

and has arbitrary quality


<strong>Breakthrough</strong> <strong>Pain</strong>:<br />

Definitional Problems<br />

• Definitional problems related to use of alternative<br />

terms<br />

– Episodic pain<br />

– Incident pain<br />

– End-of-dose failure<br />

Mercadante et al. Cancer, 2002; 94:832-839.<br />

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


<strong>Breakthrough</strong> <strong>Pain</strong>:<br />

Definitional Problems<br />

• Most studies use a version of:<br />

– A transitory, severe or excruciating pain, which lasts<br />

seconds to hours and is superimposed on a baseline<br />

pain controlled to a moderate or better intensity by an<br />

opioid regimen<br />

• Most studies in the cancer population<br />

– Explains opioid focus<br />

Mercadante et al. Cancer, 2002; 94:832-839.<br />

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


Prevalence of <strong>Breakthrough</strong> <strong>Pain</strong><br />

• Cancer<br />

– Community setting: 33%<br />

– Inpatient settings: 50-90%<br />

– Home care/inpatient hospice: 89%<br />

• Non-cancer<br />

– Primary care: 48%<br />

– US pain clinics: 74%<br />

Svendsen et al. Eur J <strong>Pain</strong>. 2005; 9:195-206.<br />

Portenoy et al. <strong>Pain</strong>. 1999; 81:129-134.<br />

Caraceni et al. Palliat Med. 2004;18:177-183.<br />

Portenoy et al, JOM, in press


<strong>Breakthrough</strong> <strong>Pain</strong>: Characteristics<br />

• Phenomenology usually similar to baseline pain, but<br />

large inter-individual differences<br />

• Frequency: < 1/day to many per hour<br />

• Most episodes brief, but may last hours<br />

• Onset usually over minutes, but varies<br />

• 50% associated with voluntary action, but some nonvolitional<br />

• May be predictable or appear without warning<br />

Mercadante et al. Cancer. 2002; 94:832-839.<br />

Caraceni et al. Palliative Med. 2004; 18:177-183.<br />

Portenoy & Hagen. <strong>Pain</strong>. 1990; 4:273-281.


Cancer-Related<br />

<strong>Breakthrough</strong> <strong>Pain</strong>: Predictability<br />

Almost<br />

always<br />

11%<br />

Often<br />

7%<br />

Always<br />

15%<br />

Sometimes<br />

19%<br />

Never<br />

48%


<strong>Breakthrough</strong> <strong>Pain</strong>: Onset<br />

• Cancer-related breakthrough pain (N=164)<br />

– Time to peak intensity ranged from 1 second to 30<br />

minutes<br />

– Median 3.2 min<br />

.


<strong>Breakthrough</strong> <strong>Pain</strong>: Treatment Issues<br />

• Guidelines based on expert opinion<br />

• Elements:<br />

– Assessment<br />

– Treatment of underlying etiology<br />

– Optimizing regularly scheduled opioid<br />

– Specific treatments for breakthrough pain<br />

• Nonpharmacologic<br />

• Pharmacologic<br />

– Nonopioid<br />

– Opioid<br />

Portenoy and Hagen. <strong>Pain</strong>. 1990; Portenoy et al. <strong>Pain</strong>. 1999; 81:129-134.<br />

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


<strong>Breakthrough</strong> <strong>Pain</strong>: Treatment Issues<br />

• Assessment Issues<br />

– Characterize baseline pain and breakthrough pain<br />

– Clarify syndrome, etiology and pathophysiology<br />

– Determine relevant <strong>com</strong>orbidities and goals of care


<strong>Breakthrough</strong> <strong>Pain</strong>: Treatment Issues<br />

• Treatment of underlying etiology<br />

– <strong>Pain</strong> etiology<br />

• Example: RT to bone metastasis<br />

– Precipitating events<br />

• Examples:<br />

– Antitussive for cough<br />

– Limb orthotic for incident pain with movement


<strong>Breakthrough</strong> <strong>Pain</strong>: Treatment Issues<br />

• Optimizing regularly scheduled opioid<br />

– Viewed as most clearly useful for end-of-dose failure<br />

– Theoretically helpful in reducing frequency or intensity<br />

of other breakthrough pains<br />

– Very few data


<strong>Breakthrough</strong> <strong>Pain</strong>: Treatment Issues<br />

• Optimizing regularly scheduled opioid<br />

– Open-label, short-term study of 25 advanced cancer<br />

patients with movement-related episodic pain<br />

• Opioid dose titrated above dose yielding pain relief at<br />

rest to dose associated with limiting adverse effects<br />

• Compared to admission<br />

– Mean baseline pain on day 1 declined from 5.28 to 1.73<br />

(p


<strong>Breakthrough</strong> <strong>Pain</strong>: Treatment Issues<br />

• Specific treatments for breakthrough pain<br />

– Nonpharmacologic<br />

– Pharmacologic


<strong>Breakthrough</strong> <strong>Pain</strong>: Treatment Issues<br />

• Nonpharmacologic treatments for breakthrough<br />

pain<br />

– Application of heat or cold<br />

– Massage or stretching<br />

– Cognitive technique like deep relaxation, mental<br />

imagery or self-hypnosis


<strong>Breakthrough</strong> <strong>Pain</strong>: Treatment Issues<br />

• Pharmacologic treatments for breakthrough pain<br />

– Nonopioid<br />

• Example: NSAID<br />

• Example: nasal or sublingual ketamine<br />

• Example: spinal local anesthetic<br />

– Opioid<br />

Carr et al. <strong>Pain</strong>. 2004;108:17-27<br />

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


Treatment of BTP using Intranasal<br />

Ketamine<br />

Numerical <strong>Pain</strong> Intensity Scale<br />

Change from Baseline<br />

0<br />

-1<br />

-2<br />

-3<br />

-4<br />

-5<br />

0<br />

Dosing<br />

Period<br />

*<br />

* *<br />

* * *<br />

10 20 30 40 50 60<br />

Time, min<br />

*<br />

*<br />

Placebo<br />

Ketamine<br />

N=20


<strong>Breakthrough</strong> <strong>Pain</strong>: Opioid Treatment<br />

• Opioid treatment for breakthrough pain<br />

– Known as “rescue dose”<br />

– Standard of care for cancer patients receiving a baseline<br />

opioid regimen for chronic pain<br />

– Used variable in the noncancer chronic pain<br />

populations<br />

– Treatment guidelines based on expert opinion<br />

– Limited data and many unknowns


“Rescue Dose” According to Expert<br />

Opinion<br />

• Expert opinion:<br />

– Drug should be identical to fixed scheduled opioid but<br />

formulation should have a short half-life, a rapid onset<br />

and short duration of effect<br />

– Drug should be given by the same route as the fixed<br />

scheduled opioid<br />

– Drug should be given at a dose that is a fixed<br />

proportion of the baseline dose<br />

– Rescue dose should be titrated over time just like the<br />

baseline opioid regimen<br />

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

American <strong>Pain</strong> Society. Principles of Analgesic Use in the Treatment of Acute <strong>Pain</strong> and Cancer <strong>Pain</strong>, 2003.<br />

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


“Rescue Dose” According to Expert<br />

Opinion<br />

• Expert opinion:<br />

– Very little supporting data for re<strong>com</strong>mendations<br />

– Advent of rapid onset formulations have questioned some<br />

assumptions<br />

• Same drug?<br />

• Same route?<br />

• Proportionate dose?<br />

– New question: When should rapid onset opioids be used


“Rescue Dose”<br />

• Most <strong>com</strong>mon approach at the present time<br />

– Oral or IV/SQ rescue doses<br />

• Same drug and route as baseline<br />

• “PRN” dose at 5-15% of the total daily dose<br />

• Offered every 1-2 hours if oral and every 15-60 minutes<br />

if IV/SQ<br />

• Dose titration is often necessary


“Rescue Dose”<br />

• Study of fixed proportion “rescue dose”<br />

– Open-label, short-term study of 48 advanced cancer<br />

patients with episodic pain receiving oral opioid<br />

regimens<br />

• IV morphine given at 20% of total daily dose for<br />

episodes of pain<br />

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

minutes<br />

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

– Adverse events un<strong>com</strong>mon and tolerable<br />

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


“Rescue Dose”<br />

• Studies of fixed proportion “rescue dose”<br />

– Controlled trials of oral transmucosal fentanyl citrate<br />

and fentanyl effervescent buccal tablet showed no<br />

relationship between size of rescue dose and baseline<br />

opioid regimen<br />

– Conclusion: Titration from low initial dose is needed<br />

for rapid onset fentanyl formulations<br />

Lichtor et al. Anesthesia and Analgesia.1999; 88:732-738.<br />

Portenoy et al. <strong>Pain</strong>.1999; 81:129-134.<br />

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


“Rescue Dose”<br />

• Study of methadone “rescue dose”<br />

– Open-label, short-term, crossover study of methadone<br />

vs. usual “rescue dose” in 6 patients with cancer pain<br />

• In 37 episodes, onset of analgesic effect was rapid; 3 patients<br />

experienced onset by 10 minutes<br />

• Adverse effect profile of oral methadone was same as usual<br />

drug<br />

• Patients were moderately to <strong>com</strong>pletely satisfied<br />

– Conclusion: Use of a long half-life drug may be acceptable<br />

in some patients<br />

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


“Rescue Dose”<br />

• New rapid onset formulations<br />

– Mismatch between phenomenology and time-action<br />

of oral drug suggested opportunity for better<br />

out<strong>com</strong>es with rapid onset formulations<br />

– Rapid onset opioids use lipophilic drug and transmucosal<br />

route to approach the time-action of an IV bolus


<strong>Pain</strong> Intensity<br />

Rapid Onset Opioids: Addressing<br />

the Mismatch<br />

Rescue Dose<br />

Baseline <strong>Pain</strong><br />

Time<br />

Around-The-Clock<br />

Medication<br />

Fentanyl<br />

(ng/mL ± SEM)<br />

400 µg I.V.<br />

400 µg FEBT<br />

800 µg OTFC<br />

800 µg Oral<br />

2.5<br />

2.0<br />

1.5<br />

1.0<br />

0.5<br />

0.0<br />

1.0<br />

0.5<br />

0.0<br />

0 1<br />

0 1 2 3 4 5 6<br />

Time, h


Rapid-Onset “Rescue Dose”<br />

• Approved formulations in the US and Europe<br />

– Oral transmucosal fentanyl citrate<br />

– Fentanyl effervescent buccal tablet<br />

– Bio-erodible mucoadhesive (BEMA ) patch<br />

– Fentanyl solution nasal spray<br />

– Sublingual fentanyl tablet


Oral Transmucosal Fentanyl Citrate<br />

(OTFC)<br />

• First rapid onset formulation<br />

• Demonstrated viability of using fentanyl<br />

• Median onset of relief = 5 minutes; peak plasma<br />

concentration +/- 22 minutes<br />

• Clinical trials demonstrate safety and efficacy<br />

• Limited <strong>com</strong>parative data<br />

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

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

2001; 22:575-583.


Study<br />

OTFC in <strong>Breakthrough</strong> Cancer <strong>Pain</strong><br />

<strong>Pain</strong> Intensity at 15 Minutes<br />

Christie 1998<br />

Coluzzi 2001<br />

Farrar 1998<br />

Portenoy 1999 a<br />

Total (95% CI)<br />

Weighted Mean Difference (Fixed) 95% CI<br />

-4.0 -2.0 0 2.0 4.0<br />

Favors OTFC Favors Control


Rapid Onset “Rescue Dose” vs. Oral<br />

Morphine: Study of OTFC<br />

• Controlled <strong>com</strong>parative trial<br />

– Double-blind, double-dummy, randomized, multiple<br />

crossover study in 134 ca patients with BTP<br />

– Compared 'successful' MSIR dose (15-60 mg) and<br />

optimally titrated OTFC<br />

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

OTFC<br />

– OTFC yielded better pain relief than MSIR at all time<br />

points that were significantly better than MSIR<br />

Coluzzi et al. <strong>Pain</strong>. 2001;91:123-130.


Fentanyl<br />

(ng/mL ± SEM)<br />

Rapid Onset Formulations: Trying to<br />

Approach the IV Bolus<br />

2.5<br />

2.0<br />

1.5<br />

1.0<br />

0.5<br />

0.0<br />

400 µg I.V.<br />

400 µg FEBT<br />

800 µg OTFC<br />

800 µg Oral<br />

0 1 2 3 4 5 6<br />

1.0<br />

0.5<br />

0.0<br />

Time, h<br />

0 1


% of Episodes with<br />

> 33% Improvement<br />

FEBT: Placebo-Controlled Trial<br />

80<br />

70<br />

60<br />

50<br />

40<br />

30<br />

20<br />

10<br />

0<br />

14<br />

9<br />

49<br />

29<br />

15 min 30 min 45 min 60 min<br />

Time (min)<br />

71<br />

44<br />

75<br />

48<br />

FEBT<br />

Placebo<br />

P < 0.05 at all time<br />

points


Episodes, %<br />

RCT of Fentany Pectin Nasal Spray:<br />

% Episodes w/ =1-Point <strong>Pain</strong> Reduction<br />

100<br />

90<br />

80<br />

70<br />

60<br />

50<br />

40<br />

30<br />

20<br />

10<br />

0<br />

33.3<br />

*<br />

26.5<br />

61<br />

**<br />

44<br />

73.2<br />

5 10 15 30 45 60<br />

*P=0.04 vs placebo.<br />

**P


Formulations in Development<br />

• Fentanyl pectin nasal spray<br />

• Aerosolized fentanyl formulations<br />

• Micro-needle systems<br />

• Morphine-chitosan nasal spray formulation<br />

• Hydromorphone nasal spray formulation<br />

• Fentanyl sublingual spray<br />

• Iontophoretic PCA patch<br />

• Sublingual or intranasal sufentanil


Rapid Onset Opioids: Concerns<br />

• Most of the use in the US is off-label<br />

• Unintentional overdose probably related to<br />

unsophisticated prescribers, wrong patient population<br />

• Separate concern about drug abuse issues<br />

– Attractiveness to those with addiction, leading to<br />

diversion<br />

– Likelihood of relapse or iatrogenic addiction<br />

• Voluntary REMS programs in the US pre-empting<br />

mandatory REMS


Opioid Treatment of <strong>Breakthrough</strong> <strong>Pain</strong>:<br />

Unresolved Issues<br />

• Conclusions<br />

– A consensus-driven treatment strategy may be helpful:<br />

• Assessment<br />

• Treating pain etiology or precipitating events<br />

• Optimizing baseline analgesic regimen, and<br />

• Using symptomatic pharmacologic and non-pharmacologic<br />

therapies<br />

– Use of “rescue doses” has be<strong>com</strong>e conventional practice for<br />

cancer-related breakthrough pain and appears to be useful<br />

– Role of rapid onset formulations is evolving


Opioid Treatment of <strong>Breakthrough</strong> <strong>Pain</strong>:<br />

Unresolved Issues<br />

• Still many unknowns<br />

– What is the “best” definition for breakthrough pain<br />

– Does the effective treatment of breakthrough pain reduce all<br />

the associated adverse events and consequences


Opioid Treatment of <strong>Breakthrough</strong> <strong>Pain</strong>:<br />

Unresolved Issues<br />

• Still many unknowns<br />

– When using opioids to treat breakthrough pain<br />

• Is dosing proportional to baseline dose necessary or best<br />

approach?<br />

• Would use of a drug different than baseline drug improve<br />

efficacy?<br />

• Do rapid onset drugs yield added benefit?<br />

• Do the rapid onset drugs pose added risk?<br />

• How should nonopioid and nonpharmacological approaches be<br />

<strong>com</strong>bined with drug therapy?

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