1. Multimodal Chronic Pain
Treatment
New Directions
N. Lee Smith MD
Center for MindBody Health
Director, Stress Medicine
Omega Pain Clinic and Lifetree Clinical Research
Salt Lake City, Utah

3. Focus
• Acute vs Chronic Pain
• Nociceptive vs Neuropathic vs Central
• The common role of central sensitization
– Prototype: Fibromyalgia
• Multimodality treatment:
– How to reduce opiates with good relief?
• Myofascial Trigger Points

4. Acute pain = a symptom
Chronic pain = a disease
If acute pain goes under-treated,
more chronic pain

5. Chronic post-surgical pain
• Thoracotomy 50-60%
• Amputation 50%
• Breast surgery 33%
• Inguinal hernia 30%
• C-section 12%
Why?
And who is more likely?
How to prevent this?

6. Pain Treatment:
How are we doing?
“Pain can be relieved effectively
in 90% of patients, but is not
relieved effectively in 80% of
patients”
Walco, New Engl J Med 1994;331:8
Chronic pain is often misunderstood

7. Acute pain is often
inadequately treated:
Why?
• Fear of opiods: MD
– 1/2 of fractures receive them
– 42% come to ER for pain:
• 3/4 leave in moderate to severe pain
• Patient fears: 3/4 prefer non-opiate

9. What percent of
chronic pain patients say,
“Opiates give me little or no
pain relief”?
53%
American Pain Foundation Survey 2007

10. Distinguishing different types of pain
Nociceptive Neuropathic
Central Caused by nerve
Caused by
tissue damage
Snsitization lesion or dysfunction
• Arthritis
• Fibromyalgia • Painful Diabetes
• Injuries
• Low back pain • Shingles, PHN
• Postoperative pain
• Neck pain • Sciatica
• Trigeminal neuralgia

11. Pain Distribution
• Use a body pain
diagram
• Have a patient color
all areas of the body in
which they feel pain
Adapted from pain drawing provided courtesy of L Bateman.
Back Front

12. Pain Distribution
Neuropathic
Back Front

13. Pain Distribution
Arthritis
Back Front

14. Pain Distribution
Fibromyalgia
Back Front

15. The Diagnosis of Fibromyalgia
Officially:
• Chronic widespread pain (> 3 months)
• Tender points (11/18 officially)
• Also
– Fatigue
– Unrefreshed sleep
– Cognitive problems
– Comorbidities
Am. College Rheumatology, Criteria for Fibromyalgia, Arthritis Rheum 33:160-172, 1990

17. Comorbidities of FM
50% of FMS patients also have
the most common disorder seen in
GI Clinics
(@ half of GI pts)

18. Comparison of pain
thresholds
IBS
Normal
Colonic
Reference: Whitehead et al. Gastroenterology. May 1990;98:1187-1192.
Distension

19. Comparison of pain thresholds
of IBS patients and controls
Pain produced by rectosigmoid balloon distension
60
IBS
% Reporting Pain
40
20
Normal
0
20 60 100 140 180
Rectosigmoid balloon volume (mL)
cf. Irritable Bladder Reference: From Whitehead et al. Dig Dis Sci. June 1980;25:404-413..

20. Central Hypersensitization-
Amplification Syndromes
• Irritable bowel syndrome
(& functional Upper Gastrointestinal pain)
• Irritable bladder More
• Migraine, tension and TM Jt. Headaches Chronic
• Fibromyalgia (or multiple pain) Syndromes Pain
• Non-cardiac chest pain
• Restless legs syndrome
• Anxiety and some depression disorders

21. How does
hypersensitization occur?
In whom is this more likely?

22. Fibromyalgia:
Contributing Factors
• Genetic predisposition
• Neurotransmission and sleep abnormalities
• Triggering events
• Disordered sensory processing

23. Neurotransmission
Issues
Inhibitory tracts
(NE, DA, 5HT)
When inhibition is
lacking, the
nervous system
hypersensitizes
SP

24. CSF Substance P in FMS
45
40
35
30
25
Normals
20 FMS
15
10
5
0
Vaeroy Russell Welin Bradley

25. Fibromyalgia: Pain Processing Disorder
fMRI Evidence: Augmentation
fMRI = functional magnetic resonance imaging.
Gracely et al. Arthritis Rheum. 2002;46:1333-1343.

26. FMS: Neurotransmission
Abnormalities (in CSF)
• Low central serotonin function
}
⇒ deep sleep loss, anxiety)
• Low central norepinephrine function
⇒ fatigue, pain, cognition ADs
• Low dopamine function
⇒ ↓attention, ↓pleasure, ↓ sex, RLS
}
• High Substance P
⇒ pain amplification ACs
• High Glutamate
Russell J Arth Rheum 1994;37:1543-1560

27. Pharmacological
Targets for
Treatment Deep sleep
Antidepressants
(NRIs)
Tramadol Inhibitory tracts
Tapentadol (NE, DA & 5HT) Dopamine
agonists
NSAIDs
If present: Anticonvulsants,
trigger SP neural stabilizers
points?

28. Grading Pain Severity
For example
• Nuisance: after exercise aches
• Distracting: menstrual cramps, OA,
finger burn residual
• Disabling: migraine, toothache
• Worst Possible: labor, severe burns, kidney stone
50%
30%
0___1____2____3____4_____5____6____7____8_____9___10
nuisancedistracting disabling worst

29. Neuropathic Pain:
>50% Reduction
7
6
5 Na ACs(CBP,OXC)
Number 4 TCAs
needed Tramadol
to treat 3 Ca ACs(PGB,GBP)
SNRIs(dulox,venla)
2 SSRIs
1
0
Na+ TCAs Tram Ca++ SNRIs SSRIs
ACs ACs Gilron et al. CMAJ 2006;175(3)
Cochrane Database SR
2006;3:CD003726

30. Anticonvulsants:
Neural stabilizers
• Sodium channel block (e.g., divalproex, lamotrigene)
• Calcium channel modulation (e.g.,pregabalin, gabapentin)
• GABA enhancers (e.g., tiagabine, baclofen)
These ↓ Glutamate release
Using meds with complementary mechanisms in lower
dose may be better than high doses of one mechanism

31. Positive Pharmacological Trials
for Fibromyalgia
• Anticonvulsants: Pregabalin (30% get 50% improvement)
• Dual action “antidepressants”: (30-40% get 50% improved)
– Milnacipran, Duloxetine, Venlafaxine
– Tricyclics (about 1/3 improve with low dose)
– Cyclobenzaprine (10-30 mg)
– Tramadol (28% reduction)
• Dopamine agonists: (75% improve; about 40% get 50% improv.)
• Gamma hydroxybuyrate (GHB) (30% get 50% improvement)
Usually, these are used in combination

32. SNRIs for Pain
• Duloxetine
– FDA indicated in four types of pain
• Minacipran
– For fibromyalgia
– More NE than serotonin

33. Tricyclics for Pain
• Second generation: more NE; fewer side effects
– nortriptylene
– desipramine
– cyclobenzaprine: better deep sleep (in low dose)

34. Opiates in Neuropathic Pain
Meta-analysis of 22 studies (n=521)
• Intermediate term (1+ months):
– VAS reduction from placebo = 1.4 / 10
– No reduction in disability or mental health scores
• In all but one study
• Short term: Sometimes helpful
(contradictory results )
Eisenberg E. JAMA 2005;293:3043-3052
One opiate is FDA-approved for neuropathic pain: tapentadol

35. How to tell if opiate responsive?
(Note well: Function)
• Good initial response: use long acting opiod
– Should be dose responsive
• If poorly responsive after 2-3 titrations:
Initiate an escape strategy
• If initially partially responsive (“Taking the
edge off”: change opiate,
and other factors need addressing
– Strongly consider an antihyperalgesic opiate

36. Two Anti-hyperalgesic Opiates:
• Buprenorphine
– Unique receptor profile
– Patch = different dosing than SL
• Tapentadol
– Weak opiate + NRI
– Indicated for both chronic pain and neuropathic pain
These two appear to have less abuse potential

37. Chronic Pain Treatment:
Opiates and NSAIDs
6
5
4
Pain Meth 5.0+Ibu 600mg
Meth 2.5+Ibu 600mg
3
Rating Methadone 5.0mg
Methadone 2.5mg
2
Change
1
0
0 0.5 hr 1 hr 2 hr 3 hr 4 hr
Ferrer-Brechner Am J Med 1984;77:78-83

38. Myofascial Pain Syndrome
is a common cause of
chronic or resistant pain
→Trigger points

44. Myofascial Pain
Syndrome: Treatment
• Principles
– 1. Inactivation of trigger points
– 2. Muscle Rehabilitation
– 3. Reduce all contributing factors

45. Myofascial Pain
Syndrome: Treatment
1. Inactivation of trigger points
• Injection of local anesthetic (lidocaine + bipuvicaine)
– Precision in placement of the needle a the point of maximal
tenderness is essential
– A local “twitch response” is usually obtained
⇒Followed by vigorous massage and stretching

46. Myofascial Pain
Syndrome: Treatment
2. Muscle Rehabilitation
• Stretching, strengthening
• Postural exercises
• Movement:
– massage, acupressure (strain/counterstrain)
These maintain the gains

47. Myofascial Pain Syndrome:
Treatment- Prevention
3. Control of contributing factors:
• Mechanical: Correct repetitive, tensing movements
– Posture and lifting improvement
• Aerobic exercise
• Stress resilience:
– Treat anxiety and depression
– Experiential cognitive behavioral resilience training

48. Who is likely to get chronic pain if
acute pain treatment is suboptimal ?
• Personal or family history of
CNS hypersensitivity disorders
– and sleep problems
• History of abuse, trauma or childhood neglect
 high CRF and sympathetic tone
For surgery in these, consider
pre-emptive analgesia

49. Pain treatment:
The earlier, the better

50. Which Medication to Start?
• Depends on dominant patterns of problems:
– Sleep + pain + tingling + anxiety: Anticonvulsant
– Pain + depression/anxiety + fatigue + cognitive: NSRI
• R/O bipolar (Add sleep agent)
– Pain alone: tramadol or cyclobenzaprine?
– Fluctuating pain + mood/anxiety or anger:
Anticonvulsant (± Atypical neuroleptic)
Often, thoughtful combinations are best

51. Treating Chronic Pain Disorders
Five important parts (interdisciplinary):
• Treat early and aggressively
• Treat CNS neurochemical hypersensitizing issues
– Anticonvulsants (3 types), dual antidepressants,
DA and alpha-2 agonists
• Treat sleep well (particularly deep stages)
• Carefully paced exercise
• Treat “stress”: Experiential cognitive-behavioral methods
• Consider trigger points
• This reduces opiate requirements and improves function

52. Self Care Websites
OFFER
Organization for Fatigue and Fibromyalgia
Education and Research
http://www.offerutah.org/
University of Michigan Fibromyalgia Center
Dr. D. A. Williams and Dr. M. Carey
http://www.med.umich.edu/painresearch/patients/self.htm

54. Neural stabilizing Nutrients
• Vitamins B6 (25-50 mg), B12 (550-1000 mcg),
methylfolate (2.5-7.5 mg)
• Omega3 fatty acids (2000 mg bid)
• Magnesium
• D-L phenylalanine (500 mg bid)

55. Sleep Stages
Non REM REM
Benzos,
Some SSR Is,
Venlafaxine 4
Blocks
3
2
1
Body repair

56. Deep Sleep Effects
of CNS Medications
• Antidepressants
– Suppress:
most SSRIs (exceptions: sertraline, citalopram)
—Trend to
suppress: venlafaxine and bupropion
– Improve: amitriptylene, nortriptylene, doxepin
cyclobenzaprine, trazodone, mirtazepine
atypical neuroleptics (TCAs and 5HT2 blockers)
tiagabine
sodium oxybate (GHB)
pregabalin and gabapentin
Citera G. Clin Rheumatol
2000;19(1):9-13

57. Why More Pain
with Anxiety and Depression?
• Up-regulated pain sensory response
– Increased Substance P
– Low CNS serotonin and norepinephrine function
– Low endorphins
• Up-regulated inflammation
– Increased prostaglandins
– Excess immune stimulation (  IL-1, IL-6 & TNF & auto- Ab)
• Excess sympathetic tone
• Loss of deep stage sleep