1. 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

2. Disclosure
The speaker cannot identify any potential conflict of interest and has no relationships that should be disclosed

3. 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

4. Pain
“An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage” (IASP)

5. The gate control theory

6. Pain pathways Brain Peripheral nociceptors Spinal cord
The key points to cover in this slide are:
The awakening of silent nociceptors in the skin, joints and muscles by the local release of chemical mediators in response to tissue damage.
The function of the “gate” mechanism in the dorsal horn of the spinal cord which allows three options for an incoming pain signal:
a) To suppress the pain signal (stress-induced analgesia)
b) To allow the pain signal to pass through to the brain unchanged
c) to augment the intensity of the pain signal sent to the brain (central sensitization)
Which of these three options occurs depends on the local balance of excitatory and inhibitory neurotransmitters It is option (c) that seems to occur in more severe, neuropathic pain syndromes.
The importance of the excitatory amino acids, especially glutamate, acting on the NMDA receptors to maintain and, in fact, augment pain signals at the dorsal horn of the spinal cord.
The function of the CNS descending inhibitory systems on pain signal transmission in the dorsal horn of the spinal cord.
Spinal cord

7. Types of pain Acute vs. chronic Malignant vs. benign
Physiological vs. pathological
Nociceptive vs. visceral
Neuropathic
Idiopathic

8. Acute vs. Chronic Pain Acute Chronic Symptom Disease Short-term
Warning sign
Anxiety
Responds well
Single treatment
Chronic
Disease
Long-term
False alarm
Depression
Less likely to respond
Multidisciplinary approach

9. 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)

10. 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]

11. 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

12. 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

13. 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

14. 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% )

15. 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)

16. The chronic pain spiral
ILLNESS
INJURY
SURGERY
STIGMA
TISSUE DAMAGE
LOSS OF CONTROL
DEPRESSION
Pain
Centered
Life
PERSISTING PAIN
DECREASED PHYSICAL & SOCIAL FUNCTIONING
The main message of this slide is to demonstrate the importance of treating a patient with pain as early as possible.
HURT VS. HARM
LIMITS ACTIVITIES
DECONDITIONING
WEAK TIGHT MUSCLES
Jovey RD. Pain focus. 2007;1.

17. Pain assessment tools Pain measurement Pain History
Psychosocial history (mood, substance abuse, functional level, family, occupation, etc.)
Goals & expectations
PQRST =
Provocative (identify pain triggers)
Quality of pain
Region of pain (location)
Severity (numeric pain scale, 0-10)
Temporal (onset, course, fluctuations)
SISAP Questions Caution with
How many drinks in a typical day? ______________ Women > 3 drinks/day or 12/week
How many drinks in a typical week? _____________ Men > 4 drinks/day or 16/week
Marijuana or hashish in the past year? ____________ Any recreational marijuana or hashish use
Ever smoked cigarettes? ___________Age ________ Any smoker under the age of 40

18. Interpreting changes in pain intensity
Decrease in pain intensity
Clinical significance
10 – 20 %
Minimal
≥ 30%
Moderate
≥ 50%
Substantial
A consensus meeting was convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) to provide recommendations for interpreting clinical importance of treatment outcomes in clinical trials of the efficacy and effectiveness of chronic pain treatments. A group of 40 participants from universities, governmental agencies, a patient self-help organization, and the pharmaceutical industry considered methodologic issues and research results relevant to determining the clinical importance of changes in the specific outcome measures previously recommended by IMMPACT for 4 core chronic pain outcome domains, including pain intensity assessed by a 0 to 10 numerical rating scale.
Dworkin RH, et al. J Pain. 2007; Article in press.

19. 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

20. Goals PALLIATION REHABILITATION SIDE EFFECTS COST AVAILABILITY
In deciding on a particular course of treatment for a patient’s CNCP, we need to think realistically about the goals. Ideally, we are trying to reduce pain and improve function with minimal side effects. However, in some patients with severe chronic pain of long duration, we may not be able to improve function to a significant degree due to severe disuse muscle atrophy or the side effects of our treatment. Sometimes we are not able to provide the ideal treatment for a given patient due to cost or lack of availability in our community.
SIDE EFFECTS
COST
AVAILABILITY
CLINICAL EXPERTISE

21. Optimize balance between analgesia and adverse effects

22. 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

23. 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

24. 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 AZ

25. Palliative therapeutic modalities
Non-pharmacological approaches
Analgesic medications
Invasive interventions

26. WHO analgesic ladder Pain Intensity weak-opioids + non-opioids
+ adjuvants
strong-opioids
+ non-opioids
+ adjuvants
non-opioids + adjuvants
III II I
Pain Intensity

27. Analgesic ladder: multimodal modification
non-opioids
+ non-invasive
measures
opioids
+ non-invasive
+ simple invasive measures
opioids
+ non-invasive
+ super invasive measures II
III I
Pain Intensity

28. Non-pharmacological measures
Psychological & behavioral therapy
CAM & diet
Relaxation, biofeedback, hypnosis
Physical modalities

29. Invasive measures Trigger point injections Nerve blocks
IV lidocaine/ketamin/bisphosphenates infusions
Spinal axis interventions
Sympathectomy

30. Super -invasive measures
Peripheral nerve, spinal cord & brain stimulation
Implanted spinal pump
Ablative surgery

31. Pharmacological modalities
Non-opioid analgesics
Opioids
Adjuvants
Marijuana and marijuana derivates

32. 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

33. Dose recommendation Tramadol/acetaminophen: 1-2 Tb. Every 4-6h
Tramadol extended release: once daily, not beyond 400mg
Reduced dose in kidney disease

34. Clinical aspects Abuse potential: Probably less than opioids
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

35. 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

36. Adjuvant analgesics Mood stabilizers & antidepressants Sleep promoters
Anti - epileptics
Marijuana derivates
Steroids

37. Antidepressants: Tricyclics - amitriptyline
Suggested mechanism:
CA reuptake inhibitors
Affinity for opioid receptors
NMDS blockers
Voltage-gated Na(+) channels blockers

38. 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

39. 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

40. 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

41. 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

42. 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

43. 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

44. Gabapentin – side effects
Common:
Somnolence
Dizziness
Ataxia, nervousness & tremor
Be aware of:
Joint & diffused body pain
Peripheral edema
Tolerance?

45. Pregabalin Beneficial in: PO pain Diabetic peripheral neuropathy PHN
Fibromyalgia
Recommended dose: mg/day
Almost as popular as Tylenol among chronic pain patients
Mostly used in Quebec off-label

46. Cannabinoids
Anonymous cross-sectional survey of 209 Canadians with chronic pain1:
35% reported using cannabis
15% reported using cannabis for pain relief
Mainly young people, post trauma/surgery
A wide range of amounts and frequency of cannabis use
Pain, sleep & mood were all subjectively improved
1Ware MA et al, Pain 102;211-6:2003

47. Cannabinoids Oral synthetic preparations:
Nabilone (Cesamet): 0.5-4mg/day
Dronabinol (Marinol): mg/day
Sativex: cannabis-based buccal spray (neuropathic pain)
Indications: - 2nd line adjuvant pain therapy
- Insomnia

48. Chronic pain palliation – Does it work?
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

49. 443 chronic DM patients treated with lipoic acid (600mg/d) for a mean period of 5 years
Switched to gabapentin ( mg/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

50. Investments in pain palliation1
1Chappell AS, et al, Pain 146;253-60:2009

51. 1Bansal D et al, Diabetic Medicine 26;1019-26:2009AZ

52. 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; :2002; 2Schwartzman RJ et al, Clin J Pain 25;273-80:2009 AZ

53. 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

54. 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

55. Outcome of injection therapy
Facet joint injections:
Not effective
Trigger point injections:
Hardly effective

56. 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

57. 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)

58. 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 AZ

59. 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 AZ

60. Preventing CNCP Prevention of CNCP Environmental contribution
Identify patients at risk
Preventive analgesia;
Multimodal analgesia; Immunization;
Other, yet to be found measures
Prevention of CNCP

61. 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

62. 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

63. Phenotypic markers Previous exposure to painful stimuli
Early life adversities
Basic sensitivity to painful stimuli1
1Granot M, et al., Anesthesiology 98;1422:2003

64. 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

65. The weather

66. The food we eat

67. 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

68. 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

69. 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; :2005

70. 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

71. 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; :2005

72. 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

73. Thank you