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Adequate therapy for chronic non-cancer pain:

Current barriers and thoughts for the future

Dr. Yoram Shir

Alan Edwards Pain Management Unit

McGill University Health Centre

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Disclosure

The speaker cannot identify any potential conflict of

interest and has no relationships that should be

disclosed

Objectives

To review the prevalence of chronic non-cancer pain (CNCP)

To review specific therapeutic approaches To recognize the barriers for better treatment To suggest changes in our approach to CNCP

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Pain

“An unpleasant sensory and emotional

experience associated with actual or potential

tissue damage or described in terms of such

damage” (IASP)

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The gate control theory

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Brain

Peripheral nociceptors

Pain pathways

Spinal cord

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Types of pain

Acute vs. chronic Malignant vs. benign

Physiological vs. pathological Nociceptive vs. visceral Neuropathic Idiopathic

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Acute vs. Chronic Pain

Acute Symptom Short-term Warning sign Anxiety Responds well Single treatment

Chronic Disease Long-term False alarm Depression Less likely to respond Multidisciplinary approach

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Non malignant vs. malignant pain

”…we have deliberately not used the term ‘non-malignant pain’ because unrelieved chronic pain associated with any disease is indeed malignant” (Gourlay et al, 1991)

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Definition: chronic non-cancer pain

“…pain that has been present for at least six months or that has persisted longer than the expected time for tissue healing or resolution of the underlying disease process.” [Canadian Pain Society Guidelines, 2002]

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Prevalence of chronic pain

> 80% of cancer patients 10-40% of the general population > 50% following some surgeries ~ 25% in hospitalized populations 45-80% of the elderly populations 25% in Canada

Pain in the elderly

In the USA, 17% of the population is 60 years or older

More than 38 million individuals in the USA are 65 years or older

By 2030 the number of persons aged 65 years or older in the USA will increase to an estimated 71 million

By 2025, 1.2 billion people worldwide will be aged 60 years or older

Prevalence of chronic pain in elderly people

Difference between community dwelling people & long term care

Prevalence 3.7%-80% 80% of old people with cancer Could be due to central degenerative changes,

muscle weakness & slower rate of tissue healing

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Burden of chronic pain

Became a global disease Worldwide crisis In the USA alone:

Half million lost workdays/annum Healthcare costs > $150 billion/annum Steady increase in cost (e.g., 70% 1988-1995)

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Chronic pain in Canada

2/3 of Canadian primary care practitioners believe that moderate/severe chronic pain is not well managed

Median waiting time for 1st appointment in multi-disciplinary pain centers in Canada is 6 months (2-14 months)

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The chronic pain spiral

PainPainCenteredCentered

LifeLife

WEAK TIGHT

MUSCLES

LIMITS ACTIVITIES DECONDITIONING

HURT VS. HARM

PERSISTING PAIN

TISSUE DAMAGE

INJURYILLNESS

SURGERY

STIGMA

LOSS OF CONTROL

DECREASED PHYSICAL &

SOCIAL FUNCTIONING

DEPRESSION

Jovey RD. Pain focus. 2007;1.

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Pain assessment tools

Pain measurement

Pain History

Psychosocial history (mood, substance abuse,

functional level, family, occupation, etc.)

Goals & expectations

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Interpreting changes in pain intensity

Decrease in pain intensity

Clinical significance

10 – 20 % Minimal

≥ 30% Moderate

≥ 50% Substantial

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Barriers to effective pain management

The physician: Believing patients always tell when having pain Lack of training/knowledge Fear of regulatory scrutiny Concerns about addiction and side effects Time consuming Pain management is secondary to disease management Believing pain is a symptom, not a disease Failure to define goals and expectations

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Goals

PALLIATION REHABILITATION

SIDE EFFECTSCOST

AVAILABILITYCLINICAL EXPERTISE

Optimize balance between analgesia and adverse effects

ANALGESIA ADVERSE EFFECTS

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Barriers to effective pain management

The patient: Misconception that pain is normal Unwillingness to report pain Fear of side effects and addiction Believing that therapy may prevent control of more

severe pain in the future Cognitive impairment in elderly Depression Passive coping strategies

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Barriers to effective pain management

The system: Lack of resources Wrongful use/investments of the existing limited

resources Lack of basic education Permissive compensatory system

The reality of CNCP

Once developed, our ability to effectively treat CNCP is restricted

Nevertheless, most traditional basic research efforts & clinical pain-relieving approaches focus on pain palliation rather than prevention

Palliative therapeutic modalities

• Non-pharmacological approaches• Analgesic medications

• Invasive interventions

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WHO analgesic ladder

I IIIII

Pain Intensity

non-opioids + adjuvants

weak-opioids + non-opioids+ adjuvants

strong-opioids +non-opioids

+ adjuvants

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Analgesic ladder: multimodal modification

I II III

Pain Intensity

non-opioids +non-invasive

measures

opioids +non-invasive

+simple invasive measures

opioids +non-invasive +super invasive

measures

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Non-pharmacological measures

Psychological & behavioral therapy

CAM & diet

Relaxation, biofeedback, hypnosis

Physical modalities

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Invasive measures

Trigger point injections

Nerve blocks

IV lidocaine/ketamin/bisphosphenates infusions

Spinal axis interventions

Sympathectomy

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Super -invasive measures

Peripheral nerve, spinal cord & brain stimulation

Implanted spinal pump

Ablative surgery

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Pharmacological modalities

Non-opioid analgesics Opioids Adjuvants Marijuana and marijuana derivates

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Non-opioid analgesics – tramadol

Centrally acting synthetic non-opioid structurally related

to codeine Tramadol/morphine potency ratio: 1:4 2 enantiomers:

(-) Tramadol – weak mu agonist (+) Tramadol - inhibits serotonin reuptake

Up to 95% oral bioavailability

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Dose recommendation

Tramadol/acetaminophen: 1-2 Tb. Every 4-6h Tramadol extended release: once daily, not

beyond 400mg Reduced dose in kidney disease

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Clinical aspects Effective in nociceptive, neuropathic & mixed pain conditions Abuse potential:

Probably less than opioids Similar to NSAID

Side effects: Serotonin syndrome Similar to opioids: dizziness, nausea, vomiting, sweating < opioids: constipation, sedation

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Nucynta

Centrally acting analgesic Dual action: μ-opioid agonist & NA reuptake

inhibitor. Potency between tramadol and morphine in

effectiveness Immediate and extended -release preparations 50mg Tb., up to 250mg/daily

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Adjuvant analgesics

Mood stabilizers & antidepressants Sleep promoters Anti - epileptics Marijuana derivates Steroids

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Antidepressants:Tricyclics - amitriptyline

Suggested mechanism: CA reuptake inhibitors

Affinity for opioid receptors NMDS blockers Voltage-gated Na(+) channels blockers

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Amitriptyline

Clinically effective in: Postherpetic neuralgia Diabetic neuropathy Tension type headache Central pain due to stroke Fibromyalgia

Common anti-cholinergic side effects Suggested dose: 10 (5) – 75mg

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Noradrenergic/serotonergic

antidepressant Could possess direct analgesic properties:

Mirtazapine (remoron) - tension-type headache Bupropion (welbutrin) - neuropathic pain Venlafaxine (effexor) – Visceral & neuropathic pain Duloxetine (cymbalta) – diabetic peripheral neuropathy,

fibromyalgia , non-radicular LBP

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Anticonvulsants

Commonly used in chronic pain Possible analgesic mechanisms:

increasing GABA inhibition modulating sodium and calcium channels inhibiting excitatory amino acids decreasing abnormal neuronal hyperexcitability

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Carbamazepine

Traditionally regarded as the gold-standard Effective in trigeminal neuralgia & diabetic neuropathy Side effect profile opened the way for gabapentin No clinical studies comparing it to gabapentin &

pregabalin

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Gabapentin Acts through increased synaptic GABA

& calcium blockade at the CNS Proven effects:

Post traumatic neuropathic pain Peripheral neuropathy PHN Preemptive analgesia for PO pain Neuropathic pain due to cancer

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Gabapentin – in what dose?

Effective dose: 900-1,800mg/day Dose range seen at the clinic: 100-9,600mg/day Suggested dose:

Start with 100mg T.I.D. Stop at 2,800/day

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Gabapentin – side effects

Common: Somnolence Dizziness Ataxia, nervousness & tremor

Be aware of: Joint & diffused body pain Peripheral edema Tolerance?

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Pregabalin Beneficial in:

PO pain Diabetic peripheral neuropathy PHN Fibromyalgia

Recommended dose: 75-600mg/day Almost as popular as Tylenol among chronic pain patients Mostly used in Quebec off-label

Cannabinoids

Anonymous cross-sectional survey of 209 Canadians with

chronic pain1:35% reported using cannabis15% reported using cannabis for pain relief Mainly young people, post trauma/surgeryA wide range of amounts and frequency of cannabis usePain, sleep & mood were all subjectively improved

1Ware MA et al, Pain 102;211-6:2003

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Cannabinoids Oral synthetic preparations:

Nabilone (Cesamet): 0.5-4mg/day

Dronabinol (Marinol): 2.5-10mg/day

Sativex: cannabis-based buccal spray (neuropathic pain)

Indications: - 2nd line adjuvant pain therapy

- Insomnia

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Switching from pathogenetic treatment with alpha-lipoic acid to gabapentin and other analgesics in

painful diabetic neuropathy: a real-world study in outpatients1

1Ruessmann HJ et al, J Diabetes Complications 23;174:2009

Chronic pain palliation – Does it work?

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443 chronic DM patients treated with lipoic acid (600mg/d) for a mean period of 5 years

Switched to gabapentin (600-2400mg/d) or D/C therapy In the untreated group 73% developed pain within 2 weeks In the gabapentin group:

45% developed side effects and stopped treatment 55% of patients tolerating gabapentin did not respond to a

dose of 2400mg/g

Investments in pain palliation1

1Chappell AS, et al, Pain 146;253-60:2009

1Bansal D et al, Diabetic Medicine 26;1019-26:2009

Outcome of chronic pain therapy

4-year community study1: Increased prevalence (45.5 to 53.8%) 79% still reported pain after 4 years

Retrospective study of patients with CRPS2: None had recovered In most- only modest symptom improvement Improvement not necessarily associated with

therapy

1Elliott AM et al, Pain 99;299-307:2002; 2Schwartzman RJ et al, Clin J Pain 25;273-80:2009

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Limitations of injection therapy for LBP

LBP will be experienced by most humans during their life

1/5 will consult her/his GP Specific diagnosis is lacking in ~ 85% The scientific evidence for many of the

interventions is lacking

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Outcome of injection therapy

Epidural steroids injection: Short term relief: NNT of 7 Long term relief: NNT of 13 The best study to date – no short or long-term

effect

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Outcome of injection therapy

Facet joint injections: Not effective

Trigger point injections: Hardly effective

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Multiple reviews of injection outcome in patients with LBP lasting for more than 1 month:

Treatment with facet, epidural or local injections was not beneficial immediately or late after the intervention

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Summary – therapies for chronic pain

The prognosis of chronic pain is frequently poor despite advanced knowledge and novel therapeutic tools

Most resources are invested in palliation and not prevention

We, therefore, could focus more on: Prevention The environment Complementary & alternative medicine (CAM)

A call for change – prevention rather than palliation

Learn from other major diseases like cancer: 1971: President Nixon declares ‘War on Cancer’1

Cancer Act approved by Congress Massive funding of cancer therapy but not cancer

prevention Cancer mortality has not decreased as expected

(10% in 2005, lower than the expected 50%)

1Sporn MB, Lancet 347;1377–81:1996

The cancer model – palliation vs. prevention

While treatment is effective for certain cancers, it ranks behind both early detection and risk-factor modification in its potential to reduce cancer mortality1

Calls to view cancer not only as a curable illness but primarily a preventable one2

1Danaei G et al, Lancet 366;1784 –93:2005; 2Bailar JC 3rd et al, N Engl J Med 336;1569–74 :1997

Preventing CNCP

Identify patients at risk

Environmental contribution

Prevention of CNCP

Preventive analgesia; Multimodal analgesia; Immunization; Other, yet to be found measures

Identifying high risk patients

The selective tendency to develop CNCP is still poorly understood

The concept of “high risk pain patient” should be recognized similar to high risk cardiac or pulmonary patients

Probably depends on genetic and phenotypic characteristics

Genetic markers for CNCP

The tendency to develop chronic pain in rats is 30-70% genetic1

Strong indications in humans: Haplotypes of the gene encoding catecholamine-O-methyltransferase (COMT) could distinguish between patients that will have low, moderate or high experimental pain levels2

1Mogil JS, et al., Pain 80;67:1999; 2Diatchenko L, et al., Hum Mol Genet 14;135:2005

Phenotypic markers

Previous exposure to painful stimuli Early life adversities Basic sensitivity to painful stimuli1

1Granot M, et al., Anesthesiology 98;1422:2003

The environment

Social conditions: Living in a socially compromised housing area

was significantly associated with increased chronic musculoskeletal pain1

1Bergman-S, et al., J Rheumatol 28;1368:2001

The weather

The food we eat

Supplementing rats with soy protein-rich diet before, but not after surgical nerve injury prevents the development of chronic neuropathic pain-like syndrome1

1Shir Y, et al., Anesthesiology 95;1238:2001

Practical approach to prevent some types of CNCP?

Be familiar with possible predictors (personal & family history, cultural, ethnical & social background, psychological risk factors)

Categorize level of risk Consider suitable preemptive (preventive) therapy Listen to your patients

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Immunization against (neuropathic) pain?

A study done in the USA1: In almost 40,000 older adults Early herpes zoster vaccination resulted in:

Reduced incidence of acute shingles (51%) Reduced incidence of chronic shingles pain

(66%)

1Oxman MN et al. N Engl J Med 352;2271-84:2005

Post herpetic neuralgia

• 1 million new cases/year in the USA• 15% will develop PHN• In patients > 70 years old the chances for PHN are

up to 70% (52)• Refractory to most common therapies

Controlling the brain

Following training humans can control activation of specific brain regions involved with nociception, resulting in significant pain relief1

1deCharms RC, et al, Proc Natl Acad Sci U S A 102;18626-31:2005

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When to refer patients with CNCP to a pain specialist?

Uncontrolled pain Significant disability A comorbid psychiatric disorder Diagnostic evaluation for unknown etiology Consultation for treatment recommendations Need for treatment modalities that the PCP cannot

provide

Thank you

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