Cancer pain:Neuropathic pain and BTcP

Sebastiano Mercadante, MDDirector

Anesthesia and Intensive Care UnitAnesthesia and Intensive Care UnitPain Relief and Palliative Care UnitPain Relief and Palliative Care Unit

La Maddalena Cancer Center La Maddalena Cancer Center Palermo – ItalyPalermo – Italy

Professor of palliative medicineProfessor of palliative medicineUniversity of PalermoUniversity of Palermo

• Cancer pain is a mixed mechanism pain, rarely presenting as a pure neuropathic, visceral or somatic pain syndrome.

• Rather, it may involve inflammatory, neuropathic, ischemic, and compressive mechanisms at multiple sites

Cancer pain is complex

Neuropathic Pain Syndromes in Cancer Patients

Tumor relatedBrachial plexopathyLumbosacral plexopathyEpidural spinal cord compressionCompressive neuropathiesSciatic neuropathy, others

Non malignant Post-Mastectomy Pain

• Occurs in 5-20% of women

• More common with axillary dissection

• Can be quite severe and disabling

• Incidence probably declining

• Treatment

• Physical therapy

• Pain medications

Neuropathy induced by CH

Vinka-alkaloids (vincristine)Taxanes (paclitaxel, docetaxel)Platinum (cis, carbo, oxali-platinum) Thalidomide

Co-treatment, high cumulative dosesPrevalence:10-100%Onset & severity depend on concomitant conditions: diabetes, alcholism, paraneoplastic

Paraneoplastic neuropathy

Autoimmune response to an antigen on a nerve cell:

- SCLC (1-30%)

- Ovarian

- Breast

Dysesthesia, pain, initially distal, asymmetric

Sensory neuropathy

May preceed

Anti-Hu (blood, nerve)

Inflammation, gliosis

Assessment- Common scales, non specific to NP, sensitive to change

♠ McGill Pain Questionnaire

♠ Brief Pain Inventory

- Specific scales, sensitive to changes♠ Leeds Assessment of NP♠ NP symptom inventory♠ NP scale

Neuropathic painIt is considered a negative prognostic factor, but not absolutely

Non responsive (Arner,1988) Poor prognostic factor (Bruera,1989)Opioid resistant (Portenoy,1989, Mercadante,1992, Jadad,1992)More likely associated to cognitive failure, probably because associated with higher doses (Mercadante,1997).Higher doses of opioids (Mercadante, 2009)

•Friends against pain & suffering

Non-opioids NSAIDs

adjuvants

Weak opioids

Non-opioids NSAIDs

adjuvants

Strong opioids

Non-opioids NSAIDs

adjuvants

Uncontrolled pain

Persisting pain

WHO analgesic ladder: still alive?

Amitriptyline in neuropatic cancer pain in patients on morphine therapy: a R-C study

Mercadante et al, Tumori 2002

Analgesic effects

No significant differences in pain intensity were found in a cross-over study, unless for “worst pain”

Adverse effects Drowsiness, confusion and dry mouth, significantly increased

Farmaci adiuvanti antiepilettici

Caraceni et al, 2000

Gabapentin dose titration in 3-7 days up to 800-1200mg, 22 pts

Decrease in global pain, burning pain, and shooting pain, as weel as allodynia...

No changes in adverse effects, decrease in myoclonus...

Gabapentin is effective in the treatmnt of cancer-related neuropathic pain: a prospective, open-label

study. Ross et al, J Palliat Med 2005

62 pts 300 to 1800 mg/day

25 Treatment - related

37 Tumor – related

Attrition rate at day 15: n = 21

Mean dose: 1200 mg/day

No differences in etiology (treatment v cancer)

Tumor-related group 97 mg/day of morphine orally (no changes)

Females more responsive?

Effectiveness of antiepileptic or antidepressant drugsWhen added to opioids for cancer pain: systematic review.

Bennett M, Palliat Med 2010

465 pts5 RCT studies (2 gabapentin, 1 amitryptiline, phenytoin, imipramine)3 observational studies (2 gabapentin, 1 valproate)

Gabapentin 1004-1395 mgAmitryptiline 50 mgOpioids kept stable or varied

Main conclusions

Opioids alone can be effective in NP Best evidence for gabapentin Reduction on >1 point, but more AEBenefit within 1 week Effect size less than that in non cancer NP (NNT and NNH different) Combination of lower dose opioid and adjuvants resultedin better outcome

Questions

Adjuvants may improve pain outomes but requires skilful prescribingLow doses combinations of adjuvants?How was NP defined ?

Pregabalin• Similar to gabapentin• More potent• Titration more feasible

•May low doses of pregabalin produce analgesia, independently from a neuropathic pain mechanism, reducing opioid escalation?

Morphine and pregabalin Morphine alone

4 weeks

CRITERIA FOR SELECTING ANALGESICS CRITERIA FOR SELECTING ANALGESICS FOR CANCER PAIN: DRIVERS IN DECISIONFOR CANCER PAIN: DRIVERS IN DECISION

Overall EfficacyOverall AE profile Individual clinical situationPretreatmentPain intensityPain mechanismOnsetComorbidity InteractionsAbuse potentialCostCultural influenceGuidelines

Breakthrough painBreakthrough pain

“..the term is typically Am-English and does not have any correspondent in other languages in Europe..”.

“..a broader and less burdened term could be

episodic or transient pain”

Mercadante & Expert Working Group of the EAPC

Cancer 2002

“The term breakthrough pain is expanding nowand more easily recognizable”

Optimisation of the opioid regimenMercadante S et al. Cancer 2002

Mercadante S, et al. J Pain Symptom Manage 2004.

• Is breakthrough pain a function of inadequate pharmacological therapy?1

– 'end-of-dose failure'    

• Does breakthrough pain occur only if baseline pain is well-controlled?

– Patients suffering with frequent daily episodes often require re-assessment of the background opioid regimen2

Mostly same location as baseline pain

Higher basal pain intensity: more episodes

Resistant pain related to the onset: spontaneous recovery

pain peaks

Well controlled pain

pain peaks

Uncontrolled pain

a: typical BP pattern, requiring rescue doses. b: uncontrolled basal pain requiring both optimization of basal analgesia and rescue doses during titration. c: changes in pain intensity of both basal analgesia and BP, obtainable after optimization of therapy

a

b

c

Ideal Breakthrough Pain Medication

• Rapid onset

• Short duration of effect

• Minimal side effects

• Noninvasive, easy-to-use

• Cost-effective

Portenoy RK, Hagen NA. Pain. 1990;41:273-281.

Oral Morphine Profile

BTP Profile Overmedication

Pain relief gap

Time (minutes)5 30 60

Pai

n In

tens

ityBTP Profile

Treating Cancer Pain–Ideal

Ideal Breakthrough MedicationAround-the-Clock

Medication

Persistent PainPersistent Pain

Time

Over MedicationOver Medication

• Mu-opioid receptor agonist 1

– Brain, spinal cord, smooth muscle

– Analgesia, sedation, respiratory depression, euphoria

• Estimated potency of 80 to 100 times that of morphine 2

1. Anderson R et al. J Pain Symptom Manage. 2001;21:397-400.2. Pereira J et al. J Pain Symptom Manage. 2001;22:672-687.

Fentanyl

BTcP Therapies: Target Product Profile

• Concentration–time profile that closely mirror the pain intensity–time profile of the BTcP episode

• Delivery systems with potential to:

– Enhance dissolution

– Enhance absorption

– Minimize the first-pass effect

BTcP Therapies: Delivery Systems

1998

2006/2008

2009

2008

Oral trans-mucosal fentanyl citrateOTFC

FENTORA®(US)/ EFFENTORA™(EU)

ONSOLIS™(US) FBSF

Rapinyl™/Abstral

(EU) SLF

2009

Instanyl™(EU) INFS

2009

Nasalfent ® (EU) FPNS

Effervescent BuccalTablet

Fentanyl Buccal Soluble Film

OralTransmucosal

Lozenge

Intranasal Fentanyl Spray

SublingualFentanyl

Fentayl Pectin Nasal Spray

• Buccal/Sublingual

– Actiq

– Effentora™

– Onsolis™

– Rapinyl™/Abstral

• Intranasal

– Instanyl™

– NasalFent®

BTcP Therapies: Delivery Systems Cont.

BTcP Therapies: Early Absorption parameters

Actiq Effentora

Onsolis

Abstral

Instanyl

Nasalfent

Dose(mcg)

400100-1600

400100-800

400100-1200

400100-800

40050-200

400100-800

Dwell Time(min)

15 15-20 N/A N/A

Cmax(ng/mL)

0.6 0.9 0.7 0.7 2.5 1.5

Tmax(min)

120(30–240)

45(20–240)

60-

-(23–240)

15(6-90)

20(5-90)

Oral morphine oxycodone hydromorphone

OTFC

Effervescent fentanyl

Oral methadone

IV fentanylIntranasal fentanyl

T0 T15 T30 T45

Intravenous morphine

Sublingual fentanyl

The rush….

.. to meaningfulpain relief

A question of minutes…

Mean duration of a BP event

peak

peak

Pts should be assessed for the presence of BtcP – DPts with BtcP should have this pain specifically assessed – DThe management of BtcP should be individualized – DConsideration should be given to treatmetn of the underlying cause of pain – DConsideration should be given to avoidance of the precipitating factors – DConsideration shoulc be given to modification of the background analgesia - DOpioids are the rescue medication pf choice – DThe dose should be determined by individual titration – BNon pharmacological methods may be useful – DNon-opioid analgesics may be useful – DInterventional techniques may be useful – DPts should have BtcP re-assessed - D

Portenoy RK, et al. Pain. 1999;79:303-312. Christie JM, et al. J Clin Oncol. 1998;16:3238-3245. Farrar JT, et al. J Natl Cancer Inst. 1998;90:611-616. Coluzzi PH, et al. Pain. 2001;91:123-130.

Main concerns about OTFC studiesin breakthrough pain

BP type ? Incident ? Activity test? 66% of the episodes with placebo did not require additional dose

medication (short-lived episodes? Placebo response?) In less 42% of episodes OTFC produced a >33% change of PI

(morphine 31.8%...). Is it an effective dose? Basal pain controlled (4 episodes/day)? BP not severe enough: Mean basal PI 4.7 (with extremes 1-9) Mean breakthrough PI: 6.8 (with extremes 2-10) Many patients failed titration and dropped out without being

considered Pts on high doses do not find a successful dose...

0 100 200 300 400 500 600 700 800

120

100

100

80

60

40

20

0

Hagen et al. J Palliat Med 2007

Dose of breakthrough oral opioid versus ATC dose from the four

studies of OTFCSignificant relationship (p<0.001)

High variability

INTRAVENOUS MORPHINE FOR BREAKTHROUGH PAIN IN AN ACUTE PALLIATIVE CARE UNIT: A CONFIRMATORY STUDY.

Mercadante, et al JPSM 2008

Even given in older pts or relatively large doses, IV-MO did not result in life-threatening AE in a large number of episodes (945 events) while being effective by patients in most cases. The mean dose of IV-M was 12 mg (95% CI 9-14 mg).In 8 episodes no changes in pain intensity were observed and a further dose of IV-M was given. The remaining pts did not require further interventions. No clinical events requiring medical intervention were recorded.

The role of nurses is of paramount importance in monitoring and collecting data to gather information for audit purposes in the unit.

N° patients 25 Age 59 (55-63)

Gender (M/F) 12/13 Basal morphine dose 120 mg (96-144)

Doses (OTFC / IV-MO) events / patients 200 / 4 9 / 6

400 / 8 5 / 3 600 / 12 14 / 5 800 / 16 6 / 1 1200 / 24 13 / 8 1600 / 32 6 / 2

OTFC VERSUS IV-MORPHINE FOR BREAKTHROUGH PAIN

S. Mercadante et al, Br J Cancer 2007

Zeppetella J. Opioids for cancer breakthrough pain: a pilot study reporting patient assessment of time to meaningful

pain relief. JPSM 2008

• 50 pts

• 250 episodes

• The dose of the oral rescue dose was on average 18% of the ATC dose

• For OTFC, the rescue dose was approximately 36% of the ATC dose

Opioid titration 100 200 400 800

Proportional doses

FBT for BTcP: dose titration versus doses proportional to opioids given for background analgesia

Outcomes: - number of successful episodes- tolerability

Conclusion

- Titration may be reduce patients' complicance

- Titration has not been “scientifically” demonstrated to be superior

- Doses proportional to the opioid basal regimen has been proven to be effective and safe with different ROO, facilitating prescription for BtcP in ambulatory and home care patients

Conclusion

BP should be separately evaluatedCharacteristics stressedOptimization of opioid therapyDouble prescription: specific as neededChoice according to timing and patient’s preferenceSelected cases require more expertiseMore data needed on new technologies