The Challenges of relieving cancer pain in 2014

Bernard J. Lapointe, MDEric M. Flanders Professor of Palliative Medicine, McGill University, Montreal,

Canada

Potential conflict of interest

• During the last two years period:– Consultant for NeoMed Institute.– Co-lead investigator of Tectin for Cancer Pain

sponsored by Wex Pharmaceuticals.– Consultant for Teva Pharmaceuticals Canada

© Bernard Lapointe

The relief of cancer pain remains a true challenge in 2014

• According to a meta-analysis of literature, almost 50% of cancer patients are under-treated. See Dandrea, Ann Onc, 2008

• WHO 1986 recommendations lead to an efficacious pain management for about 80% of patients living with cancer

• However this means that for 20% of our patients existing approaches do not bring the expected benefit

• Prevalence on the rise (more than 2 millions North Americans diagosed with cancer in 2013)

• One Canadian on four will develop cancer.

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• Improve quality of life• Reduce pain intensity• Improve functional

capacity. – physical– psychosocial

• Minimal side-effects

PAIN MANAGEMENT GOALS:

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PainfulStimulus

ANTINOCICETIVE: decrease intensity of ascending nociception

ANALGESIC: amplify the natural inhibitory patways

Modify Pain Perception:

Descending Pathways

Ascending Pathways

Treatment Modalities• Provide an explanation• Raise the pain threshold• Provide a psychological intervention• Modify lifestyle• Modify the pathological process

– Usually good disease control equals good symptom control– Surgery– Chemotherapy, hormone therapy, immunotherapy– radiotherapy

• Modify pain perception– Anti-nociception– analgesia

• Interrupt pain pathway (nerve block)

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Psycho-behavioural interventions

• Provide an explanation and education• Impact on the intensity of pain• Higher satisfaction toward care received• Less undesirable side-effects.

• Raise pain threshold• Sleep, anxiety, depression• Distraction, support• Intervention by psychologist often very helpful• Role of hypnosis

• High level of evidence for psychosocial interventions documented in current systematic review. See Sheinfeld-Gorin, Jclin Onc, 2012

Primary intent treatment

• Chemotherapy• Surgery• Radiotherapy• In the case of concomitant infection,

antibiotherapy

Bone Related Cancer Pain new model

• Multiple sources of nociception – Inflammatory reaction surrounding the tumor– Secretions of the tumor ( NGF)– Osteoclast activity in the case of tumor related

bone pain– Damage to nervous system

• Peripheral• central

Cancer pain model. Antinociception.

Nerve growth factor (NGF) induces sprouting and neuroma formation by sensory and sympathetic nerve fibers in a model of skeletal pain. When GFP+ tumor cells invade the periosteum, they induce ectopic sprouting of CGRP+ sensory fibers (D, arrow) and the formation of neuroma-like structures.

Tumor derived products• Prostaglandins• Endothelins• Tumor Necrosis Factor (TNF)• Interleukins IL-1 and IL-6• Epidermal growth factor• Nerve Growth Factor:

– Ability to directly activate sensory neurons expressing TrkA receptors– Modulate also the expression of large number of molecules and proteins

( substance P, cgrp, bradikinins)– Appears to be involved in

• Upregulation• Sensitization• Disinhibition of multiple neurotransmitters, ion channels in afferent nerve

and DRG fibres• 80% of C fiber innervating bone carry TrKa compared to 30% of C fibers

innervating skin

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Novel target: Trk receptor(tropomyosin-receptor-kinase)

• Tanezumab– is a monoclonal antibody

against nerve growth factor

• Currently phase 3 trials in bone related cancer pain ( breast and prostate)

• Other trials on chronic pain syndromes

Preventive or late administration of anti-NGF therapy attenuates tumor-induced nerve sprouting, neuroma formation, and cancer painJuan Miguel Jimenez-Andradea, Joseph R. Ghilardib, Gabriela Castañeda-Corrala, Michael A. Kuskowskic, Patrick W. Mantyha, b, d, Corresponding author contact information, E-mail the corresponding author, Pain 2011

Cancer pain model. Antinociception.

Dealing with inflammation

Acidosis in bone cancer pain• Acidosis triggers ASIC2 and TRPV1 receptors

• Inflammation lowers the pH • Osteoclasts maintain acidic micro-environment• Inflammation surrounding tumour as well

contributes to maintain an acidic micro-environment.• The role of the vanilloid receptor TRPV1

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corticosteroids

• Very useful when there is a ‘pain crisis’• ‘cooling effect’• Relative risks and benefits of the various

corticosteroids are unknown– Dexamethasone is often selected because of low

mineralo-corticoid– Methylprednisolone

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Non-steroidal anti-inflammatory agents:

• Ceiling effect• start treatment at the lowest recommended dose• wide inter-individual variability• monitor closely patients ( acute renal insufficiency)• Cytoprotection of gastric mucosa is indicated• Clear evidence to support superior safety or efficacy

of one NSAID over another is lacking.

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Cancer related bone pain• Dramatic proliferation of

osteoclasts at the tumor bone interface

• Pain intensity correlates with tumor growth and progression of tumor induced bone destruction

• Secretion of humoral and paracrine factors by tumors cells stimulates osteoclast activity

A new target: OPG-RANK-RANKL

• In animal experiments, RANKL inhibition disrupted the ‘vicious circle’ of bone corrosion and growth of the tumor.

• In 2012 two important publications:– RCT denosumab vs zoledronic acid in 2046 patients effect on pain. Statistically

significant 4 month delay in progression to moderate/severe pain observed with denosumab. Cleeland, Cancer 2012

– Combined analysis of 3 RCTs. Denosumab superior to zoledronic in delaying time to skeletal complication. Lipton, Eur J Cancer, 2012

• OPG and OPG-ligands RANK ligands are a promising future treatment options for the prevention and treatment of cancer pain and skeletal complications due to bone metastasis.

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Osteosarcome murin et OPG

Pharmacological targets (cancer related pain)

• Inflammation• Tumoral secretions (NGF, Cgrp, PGE2)• RANKL, RANK, OPG (bone metastasis)• Vanilloïd Receptors TRPV1

• Voltage gated Na+• Voltage gated Ca++

• Opioid receptors• Cannabinoid receptorsCB1• 5ht3 receptors( sérotonergiques )• Alpha-2 adrenergic receptors (adrénaline)• Glutamate receptors (NMDA )

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Features of an Ideal Pain Medication?

• Highly effective• Quick onset of action• Long duration

• Good tolerability • Low abuse potential

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3severe

The WHO analgesic ladderThe WHO analgesic ladder

2moderateto severe

1mild to

moderate

Nonopioid (paracetamol / NSAIDS

COX2 inhibitor) adjuvant

Nonopioid (paracetamol / NSAIDS

COX2 inhibitor) adjuvant

Opioid for moderate pain nonopioid adjuvant

Opioid for moderate pain nonopioid adjuvant

Opioid for severe pain nonopioid adjuvant

Controversial aspects Second Step of WHO analgesic ladder

• Lack of definite proof of efficacy of weak opioids ( codeine, tramadol, dihydrocodeine) for cancer pain. See ESMO, 2012

• Ceiling effect• We need randomized studies• Many authors have proposed the abolition of

the second step of the ladder in favour of the early use of a step III opioid ( morphine, oxycodone, hydromorphone ) at low dose.

© Bernard Lapointe

Strong Opioids for cancer pain

• Opioids produce analgesia through interactions with three major opioid receptors: µ, Ķ, ɖ

• Multiple distinct opioid receptor subtypes have been described

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Inter-individual variability in the response to Opioids

• Wide variability which has implications for our practice (Pasternak, JCO, June 2014)

• Eg: redheads have mutated melanocortin receptors– Show increased pain tolerance– Show also increased analgesic response to opioids.

• Inter-individual variability in the response to one single agent. Raises the question of combination of opioids. See Davis, Expert Opinion, 2012.

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Opioids commercialized in Canada

PO(ir) IV PR LC TD TM APMorphine X X X XOxycodone X X XOxycodone/naloxone XHydromorphone X X X XFentanyl X X X XTramadol X XCodéine X XMeperidine X XMéthadone X X (X) XSufentanil X XTapentadol XBuprenorphine X X

PO : voie orale; IV : voie intraveineuse ou sous-cutanée; PR : voie rectale; LC : libération contrôlée;TD : voie transdermique; TM : transmuqueuse; AP : action prolongée

First line opioid options for step III

• Morphine• Concerns arising about poor and variable oral bioavailability and the

presence of pharmacologically active metabolites. See McPherson, IASP, Pain2012

• Hydromorphone• Oxycodone• Fentanyl• All have similar efficacy and side-effects for moderate to

severe cancer pain. However opioid selection is based on consideration of:– Patient-related variables– Drug-related variables

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Opioid rotation (switching)

• Opioid rotation is considered when:– Avoid tolerance– Inadequate analgesia when despite dose increase– Intolerable adverse effects develop

• Despite lack of solid evidence it is generally accepted as clinical practice

• Most controversial drug for switching is methadone and vast majority of studies with this drug.

• Some guidelines published. See Fine, Portenoy, J Pain Symptom Manage 2009

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Combination of step lll opioids

• Use of a single strong opioid in cancer pain management has been common practice for decades; however it is evident that opioid prescribing practice is in a degree of metamorphosis.

• Systematic review published EAPC. Weak recommendation. See Fallon Pall Med 2010.

• Implications for patient• Need for more studies (gulf between the bench and the

clinic)

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methadone

• 2013 more controversies– Has a unique pharmacology– Due to highly variable and prolonged half-life, methadone

has the highest risk of among opioids of accumulation and overdosage

– Marketed in most of the world as a racemate mixture• D-isomer being a relatively potent N-methyl-D-aspartate inhibitor

and not an opioid• Can prolong QTc interval

– Analgesic role of methadone in treating cancer-related pain remains to be supported by strong evidence. Currently the data allows for a weak recommendation.

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• Combination of level III opioid with methadone• Some data beginning to be published

– Letters to editor (10- 3 cases) Haughey McKenna J. Pain Sym Man 2011, 2012.

– Retrospective analysis 16 cases. Wallace J Pallmed 2013• Potential benefits:

– Practical and safe– Avoid having to calculate an equi-analgesic dose– Low doses of methadone at the start ( 1,5-6mg / 24hrs)

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Characteristics of Breakthrough Pain

1) Moderate to severe intensityNo relation to intensity of the background (chronic)

pain

2) Rapid Onset ( usually peak intensity 5-10 minutes)

3) Short Duration (generally less than 30 min.)4) Occurs Frequently ( more than 3-4 episodes

day)Portenoy RK and Hagen NA. Pain 1990;41:273–281.

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Pharmacological management of breakthrough cancer pain

• Current approaches to the pharmacological management of BTcP include the optimization of basal analgesia.– titrating dose of long acting opioid to improve analgesia of

baseline pain ( particularly if numerous episodes)• This might increase prevalence and severity of sedation at rest.

– addition of rescue analgesia:- immediate-release opioids

– adjuvant therapies ( to prevent episodes eg. Gabapentinoid in prevention of neuropathic pain flare-ups)

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The classical approach.

•Standard recommendation: 1/6 to 1/10 of 24hr dose of ATC opioid. Usually q 1h prn.

•However, it is more and more evident that there is very little relationship between the intensity of the ATC pain and the paroxystic nature of certain episodes of BTcP. Thus the need to individualized titration.

Davis, Mellor P. et al. Lancet Oncology. 2005

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The classical approach fails many patients

• Breakthrough pain can be sudden in onset, severe, and of brief duration leading to a clinical challenge– Average time to meaningful pain relief is 30-45 min for po opioids

(whereas the average duration of breakthrough pain in these patients is 35 min)

• For example oral morphine immediate release:– Time to onset of analgesia of approx 30 minutes– Takes 1,1 hour to achieve maximal plasma conc. (Cmax)– Extensive first pass metabolism and poor bioavailability

• A range of other routes, drugs and drug delivery systems have been evaluated – Faster relief of pain – Hopefully shorter half-life

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Methods of Administration• Oral transmucosal opioids

– Rapid absorption, convenient (some formulations more than others)

• Inhaled – Lungs present large surface for drug absorption– Inhalation may be difficult for certain patients

• Intranasal– Rapid onset of action– The nose is able to accommodate a relatively small volume of drug

• Sublingual– Rapid absorption, convenient– Sublingual absorption must be rapid, limited space therefore relatively

small volume of drug

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Characteristics of opioids used for breakthrough pain

Opiod Analgesic onset (min)

Availabilty (%)

Oral morphine 30-45 30

Oral oxycodone 30-45 40-50

OTFC 15 50

FBT (buccal tablet) 15 65

SLF (sublingual) 15 70

INFS (intranasal) 5-10 70-90

FPNS (f pectin nasal) 5-10 70-90

Which formulation to select.

• Although the efficacy of all of the available agents for BTP has been demonstrated by RCTs, a lack of head-to-head evaluations makes it challenging for physicians to select based on efficacy alone.

• Meta-analysis have been attempted byt differences between populations studied and design prevent comparison.

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Safety / tolerability

• It must be emphasized that fentanyl is a highly potent opioid, the use of which leads to peak concentrations similar to those of intravenous administration, and thus needs to be handled responsibly by both doctors and patients.

• There are case reports of misuse. Nunez-Olarte.jpainsymman,2011

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Evidence based recommendations:

• The data permit a strong recommendation that pain exacerbations resulting from uncontrolled background pain should be treated with additional doses of immediate-release oral opioids, and that an appropriate titration of around the clock opioid therapy should always precede the recourse to potent rescue opioid analgesics.

• Breakthrough pain can be effectively managed with oral immediate-release opioids or with buccal or intranasal fentanyl preparations.

• In some cases the buccal or intranasal fentanyl preparations are preferable to immediate-release oral opioids because of more-rapid onset of action and shorter duration of effect.

Use of opioid analgesics in the treatment of cancer pain: evidence-based recommendations from the EAPC, 2012.

Evidence based recommendations:• Recommendations:• Immediate release formulation of opioids must be used to

treat• exacerbations of controlled background pain [I, A].• Immediate release oral morphine is appropriate to treat

predictable episodes of BTP (i.e. pain on moving, on swallowing, etc.) when administered at least 20 min beforesuch potential pain triggers [II, A].

• Intravenous opioids; buccal, sublingual and intranasal fentanyl drug delivery have a shorter onset of analgesic activity in treating BTP episodes in respect to oral morphine [I, A]– ESMO Cancer Pain, Annals Oncology, 2012

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Evidence based recommendations:• Key results available data suggest that both oral and nasal

transmucosal fentanyl citrate are safe and effective (compared with both placebo and morphine) in relieving breakthrough pain.

• The side effect profiles of oral and nasal transmucosal fentanyl citrate were similar to other opioids.

• Recommendations are made about future clinical trials. Quality of the evidence We could wish for more consistency in study design and more studies comparing the oral and nasal transmucosal fentanyl citrate formulations to one another. – Cochrane Review, Opioids for the management of breakthrough pain

in cancer patients -2013

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Take Home messages

Choice of formulation remains aleatory. No head-to-head comparisons

No correlation between background pain and intensity of the BTcP

Always titrate to relief of episode

Never use in an opioid naïve patient

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Take home messages:

• ALWAYS evaluate the risk for substance abuse in every patient.

• Despite recent publication of a study concluding that SLF given in doses proportional to the basal opioid regimen for the management of BTP is safe and effective ( see Mercadante,CMRO,2013): Titration strategies should always be established following recommendations of the manufacturer.

• Again most studies have shown no meaningful relationship between the effective dose of transmucosal opioid and the around-the-clock scheduled medication.

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Symptomatic Management of Breakthrough Pain

• Prevalence is reported with a wide range ; 19-95%• Breakthrough pain can be sudden in onset, severe,

and of brief duration leading to a clinical challenge– Average time to meaningful pain relief is 30 min for po

opioids (whereas the average duration of breakthrough pain in these patients is 35 min)

• A range of other routes, drugs and drug delivery systems have been evaluated – Faster relief of pain

Davis, MP et al. Lancet Oncol. 2005;6:696-704

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A word of Caution:

• The various new formulations of transmucosal Fentanyl for BTcP are not equianalgesic and are not therefore interchangeable.

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Should our prescriptions change when offering Supportive care ?

• Long term effects of the prescription of strong opioids never questioned in the past when we only treated terminally ill patients

• Today:– Patients undergoing active treatment– Patients in remission

• Prevalence of opioid misuse is unknown in cancer patients. Is it that different from that of chronic non-malignant pain ?

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Non-Neuronal Effects of Morphine

• Morphine has been demonstrated to up-regulate release of growth factors and other agents within the CNS and periphery known to:– Mediate enhanced pain sensitivity– Modulate bone remodelling– Modulate tumour growth

• King, T, University of Arizona. IASP, Chicago June 3-4, 2009

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Numbers needed to treat in peripheral and central neuropathic pain

Adjuvant analgesics used for neuropathic pain

• Adjuvant analgesics improve pain control within 4-8 days when added to opioids to manage cancer pain. See Bennett Pall Med 2010

• Tricyclic antidepressants.• Efficacy is independent of their antidepressant effect.• Action on descending modulatory inhibitory controls• Most common side effects are anticholinergic and can also cause cognitive

disorders of confusion in elderly. Nortriptyline preferable. • Starting dose 10-25 mg qHs

• SNRIs• Duloxetine, venlafaxine• Discontinuation rate 15-20%• Duloxetine starting dose 30mg, to60-120mg die, venlafaxine high dose 150-

225mg/d useful. see Attal, Cont Lifelong Learning Neurology 2012.

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Adjuvant analgesics used for neuropathic pain

• Alpha-2-delta ligand agonists.• Gabapentin and Pregabalin.

• Action on calcium channels• Side-effects include dizziness, somnolence, peripheral

edema, weight gain, dry mouth• Reduced dosage in renal insufficiency

• Older anticonvulsants– Valproic acid.

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• Chronic gabapentin administration attenuates ongoing and movement-evoked pain behaviors and improves ambulatory scores in mice with bone cancer

C.M. Peters, Experimental neurology 2005

Emerging treatment for neuropathic pain

• Cannabinoids.• Therapeutic potential extensively investigated in chronic pain.• In Canada oro-mucosal formulation of nabiximols ( THC-

cannabidiol) and oral nabilone• Adverse effects: dizziness, dry mouth, sedation, fatigue, gi effects.

• Botulinum Toxin Type A.• May have analgesic effect independent of its action on muscle

tone, possibly by acting on neurogenic inflammation.• Three single-center RCTs reported long-term (3 months) efficacy

of a series of subcutaneous injections (from 100-200u). See Xiao, Pain Med 2010.

© Bernard Lapointe