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Common Chronic Pain Syndromes Across the Lifespan

Kim Dupree Jones PhD, FNP-BC, FAAN

How to Optimize Management without an

Adequate Scientific Basis

US Costs of Common Chronic Conditions

Continuum of Chronic Pain

C Maxwell & K Jones 2014

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The Clinical Expression of Chronic Pain is Widely Variable

Mild, fewer

symptoms and

easily controlled

Severe, treatment

resistant and very

complex

Need an Individually

Tailored Program of

Interdisciplinary

Management

Perrot & Russell, 2014, Eur J of Pain; Paiva & Jones, 2010, Best Practices Rsch Clin Rheum

Validation/Education/Goal Setting

Tramadol/Pregabalin/Duloxetine

Exercise Advice

Chronic Pain Conditions Have Overlapping Pain Pathophysiology

Common Pain Pathways

Facilitatory

Ascending• NMDA-glutamate• Substance P-NK-1• Nitric oxide

Inhibitory

Descending• Norepinephrine• Serotonin• GABA• Opioids

– Endorphins– Enkephalins

Descending Pain Pathway

Thalamus

Hypothalamus

Processing Perception

of Pain

SpinalCord

DorsalHorn

Muscle Tissue(periphery)

Nociceptor

BrainStem

RapheNuclei

Cortex

Periaqueductal gray (PAG)

Ascending Pain Pathway

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spine painpelvic painfunctional abdominal pain/irritable bowel irritable bladder TMDheadaches myofascial painfibromyalgia

If your patient has one of these chronic non-malignant pain disorders, they are ahead of the scientific curve

Chronic = Incurable

Managing provider expectation

and patient activation are key

to successful partnership

Dizziness

Irritable bowel

Irritable bladder

Autonomic dysfunction

Restless legs

Multiple sensitivities

HeadachesCognitive dysfunction

Depression / Anxiety

Paresthesia

Insomnia Jaw pain

Severe fatigue

Exercise intolerance

Chronic pain is rarely

single site or single

symptom

Carnes et. al, 2007, Rheumatology

Symptom Impact Questionnaire

Directions: For each of the following 10 questions, check the one box that best indicates the intensity of the following common symptoms over the last 7 days.

• Criteria:

Bennett RM, Friend R, Jones KD, (2009)The Revised Fibromyalgia Impact Questionnaire (FIQR): validation and psychometric properties. Arthritis Res Ther.On-line calculator available at http://www.fiqr.info/FIQR-CALC.htm

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Bennett RM, Friend R, Jones KD, Ward R, Han BK, Ross RL. The Revised Fibromyalgia Impact Questionnaire (FIQR): validation and psychometric properties. Arthritis Res Ther.2009;11(4):R120On-line calculator available at http://www.fiqr.info/FIQR-CALC.htm

Scores and Fibromyalgia Severity

Fibromyalgia Impact Questionnaire-Revised

Tying Medications to MechanismClass Mechanism Medication Pain Sleep Fatigue Mood

SNRI Increase concentration of Serotonin andNorepinephrine

Venlafaxine + + + ++

Milnacipran* + + ++ ++

Duloxetine* + + + ++

TCA Increase concentration of Serotonin andNorepinephrine

Amitriptyline + ++

Cycolbenzaprine + ++

Nortriptyline + +

SSRI Increase concentration of Serotonin

Fluoxetine ++

Paroxetine ++

Other NE and Dopamine Buproprion + ++ ++

Anti-epileptic

Decrease release of excitatory neurotransmitters

GabapentinPregablin*

+ + + +

Analgesic NE & 5HT, weak mu agonist Tramadol ++ + +

Sodium Oxybate

Gaba, CNS depressant Xyrem ++ ++ + +

NSAIDs

Non-steroidal anti-inflammatory drugs constitute the number one class of agents used to treat fibromyalgia1

No evidence of effectiveness as monotherapy for fibromyalgia– May be modestly helpful combined with a tricyclic antidepressant2

“Since fibromyalgia is not an inflammatory disease, it is not surprising we have a lot of treatment failures”3

Chronic analgesic use can set up cycle of rebound headaches, complicating fibromyalgia management4

Useful for inflammatory comorbidities??

1. Clauw DJ. J Clin Rheumatol. 2007;13:102-109.

2. Goldenberg DL, et al. Arthritis Rheum. 1986;29:1371-1377.

3. Griffing GT. Medscape J Med. 2008;10(2):47.

4. Chakrabarty S, Zoorob R. Am Fam Physician. 2007;76:247-254.

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Tramadol

Tramadol has some mu-opioid and SNRI activity:

– Efficacious, for patients not on opioids

• Number one agent recommended by consensus statement from EULAR, 20082

Not a controlled substance Available short acting and long acting

– Nausea better tolerated in fixed-dose combination with acetaminophen3

– Limiting side effect is nausea (Zantac), +/- skin rash3

– Risk of serotonin syndrome when combined with SSRIs/ SNRIs and triptans; seizures in patients using neuroleptics, or other drugs that decrease seizure threshold4

2. Chu LF, et al. Clin J Pain. 2008;24:479-496.3. Bennett RM, et al. Am J Med. 2003;114:537-545.

4. Goldenberg DL. Best Pract Res Clin Rheumatol. 2007;21:499-511.

Tramadol/APAP

– Each tablet contains:

• 37.5 mg tramadol*

• 325 mg acetaminophen

– Not scheduled

– Not an NSAID or COX-2 NSAID

– Current indication is short-term management of pain (5 days)

– Do not use with history of seizure disorder

* 25% less tramadol

Opiates

Limited, randomized, controlled clinical trials1

Opiates may heighten pain sensitivity (opioid-induced hyperalgesia)2

Opiates may be associated with cognitive dysfunction, constipation, dose escalation and tolerance; addiction and diversion rare in FM

– Yet, #1 medication ranked by nearly 3000 FM patients in survey 3

– American Pain Society recommends long acting, compared to short acting medications for many chronic pain states

– Consider using non-narcotic, adjunctive medications to reduce the total opioid dose

– As better therapies emerge, opiate use will decline

1. Clauw DJ. J Clin Rheumatol. 2007;13:102-109.2. Chu LF, et al. Clin J Pain. 2008;24:479-496.

3. Bennett, RM. BMC Rheum. 2007.

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Opioid Withdrawal Protocol

Meds to relieve withdrawal symptoms

� Analgesic: tramadol, pregabalin– Clonidine relieves autonomic symptoms

– Benadryl , Unisom or Trazadone to relieve insomnia

– Dicyclomine for abdominal cramps

– Zofran or phenergan for nausea

– Imodium for diarrhea

Antiepileptics (Alpha-2-Delta Ligands):Pregabalin and Gabapentin

Mechanism:– Bind to α2δ subunit of voltage-gated calcium channels– Reduce calcium influx and inhibit release of neurotransmitters (eg,

glutamate, substance P)– Hypothesized to work on ascending pain pathways

Indications:– Postherpetic neuralgia (both agents)– Adjunctive therapy for partial onset seizures (both agents)– Pain associated with diabetic peripheral neuropathy (pregabalin)– Fibromyalgia (pregabalin)

Crofford LJ, et al. Arthritis Rheum. 2005;52:1264-1273.

Pregabalin 14-Week Fixed-Dose FM Trial: Significant Improvement in Pain

*600 mg/day of pregabalin is not an approved dose fo r FM; †P<0.01; ‡P≤.0125.End point mean pain score based on modified baseline observation carried forward approach (BOCF). Baseline mean = 6.7 (moderate to severe pain). P value–based LS means using MMRM ANCOVA.

Scored 0-10, lower score represents improvement. Arnold et al. APS 2007; Data on file. Pfizer Inc, New York, NY.

††

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0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 EP

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Placebo (n=184)Pregabalin 300 mg (n=183)Pregabalin 450 mg (n=190)Pregabalin 600 mg (n=188) *

‡‡‡

†† †

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Effect of Duloxetine on AveragePain Score: ≥30% Improvement

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% o

f Pat

ient

s

Russell IJ, et al. J Musculoskel Pain. 2007;15(suppl 13):58. Abstract 103.

*†

*P≤0.05 vs placebo. †P≤0.01 vs placebo.

50.7 47.252.1 49.3

36.0 37.4

0

10

20

30

40

50

60

3 Month 6 Month

Duloxetine 60 mg/dDuloxetine 120 mg/dPlacebo

Effect of Milnacipran onComposite Response : ≥30% Improvement

Pain End Points

*† †

*

% o

f Pat

ient

s

3 Months 6 Months

*P<0.05 vs placebo. †P<0.001 vs placebo1. Clauw DJ, et al. Clin Ther, 2008;30(11) 1988-2004.2. Mease PF et al. J Rheumatol 2009;36(2):398-409.

45% 44%45% 45%

27% 28%

01020304050

Milnacipran 100 mg/dMilnacipran 200 mg/dPlacebo

Antidepressants for Chronic Pain:Which To Choose?

Most studies using antidepressants as analgesics for chronic pain demonstrate effects on pain that are distinct from effects on mood1

Tricyclic antidepressants– Block reuptake of serotonin and/or norepinephrine– Low doses may effectively treat pain, poor sleep, fatigue2

– Tolerability issues; initiate therapy at very low doses, then titrate slowly1

Selective serotonin reuptake inhibitors– Better side-effect profile than TCAs– Used at higher doses, the older, less-selective SSRIs are generally more efficacious

than “highly selective” agents1,3

Dual receptor inhibitors– Inhibit both serotonin and norepinephrine– Unlike TCAs, generally no significant activity at other receptors; better tolerability1

– May have better analgesic effect than pure serotonergic drugs1

Two SNRIs have undergone multicenter trials in fibromyalgia: duloxetine and milnacipran (both FDA-approved therapies)

1. Clauw DJ. J Clin Rheumatol. 2007;13:102-109; 2. Arnold LM, et al. Psychosomatics.2000;41:104-113; 3. Fishbain D. Ann Med. 2000;32:305-316.

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Spaeth & Bennett, 2012, Ann Rheum Dis

Painp= 0.002 or <0.001

Fatiguep=<0.001

Jenkins sleep: 16 to 11, p<0.001

4 lb wt loss

71% met PGIC goal

1 year continuation:

Responder analyses showed that 68.8% of patients achieved ≥ 30% reduction in pain VAS and 69.7% achieved ≥ 30% reduction in FIQ total score at study endpoint

Arth Rsch Ther 2013

Marijuana / Marijuana Derivatives

Add text here

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Summary Of Evidence For Efficacy Of Pharmacologic Therapies

1Clauw DJ. J Clin Psychiatry. 2008;69(suppl 2):25-29. 2Chakrabarty S and Zoorob R. Am Fam Physician. 2007;76:247-254.3Goldenberg DL, et al. JAMA. 2004;292:2388-2395. 4Russell IJ, et al. Arthritis Rheum. 2009;60:299-309. 5Staud R. Drugs. 2010;70:1-14.

Currently FDA-approved for FM 5: duloxetine; milnacipran; pregabalin

Strong Evidence• α2δ ligands

(pregabalin, gabapentin)1

• Dual reuptake inhibitors (SNRIs, duloxetine, milnacipran)1

• Tricyclics and related agents (amitriptyline, cyclobenzaprine)1-3

• Sodium oxybate4

Moderate Evidence• SSRIs (fluoxetine ±

amitriptyline, paroxetine)1-3

• Tramadol ±acetaminophen1-3

• Pramipexole1

Weak/No Evidence• Nonsteroidal anti-

inflammatory drugs1-3

• Opioids1-3

• Corticosteroids2,3

• Benzodiazepines1,3

• Phenteramine• Pindolol• Amantadine• Namenda

Can’t treat Overall Pain? Treat a Pain Generator: Migraine Preventatives

More than 2 migraines per week or more than two migraine headache days per week

1. Propanolol* 60mg SR (NOT short acting) one to three a day

2. Amitriptiline 25mg q hs and increase to at least 75mg q hs

3. Zonegran 100-200mg bid

4. Long acting NSAIDS

5. Consider posture and trigger point therapy

*Class A Evidence

Migraine Abortives

• Imitrex 50 or 100mg, Maxalt MLT, Frova* 2.5mg to be taken right at onset and again two hours later (no more than two in 24 hours)

• Can pair with Naproxen 500mg or other shorter acting anti inflammatory, caffeine or tylenol for very effective non narcotic therapy

• Zofran for nausea

• Benedryl 25mg, Tramadol 50mg can also be added

* Class A Evidence

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Treat Regional Pain Sources

Myofascial Trigger Points:

exercise

self-care

Injection/dry needling

massage

myofascial release

Myofascial Trigger Points

It is important to eliminate myofascial

trigger points

Myofascial “Web”

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Connective Tissue that Envelopes Muscles

MFR is Not Massage

Myofascial Release for FM

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Castro-Sanchez et al . 2011

� 20 weeks myofascial release therapy

� Compared to sham ultrasound

� Significant improvement in pain and tender

points

� Pain reduction persisted at 1 and 6 months post-

intervention

25th Anniversary of Exercise Interventions in Fibromyalgia

> 135 original studies

> 6,200 subjects

6 + systematic reviews

4 notable narrative reviews

Busch et al., 2009, Int J of Clin Rhem & Busch et al., 2010, Curr Pain Headche Rep

What Improves in Fibromyalgia During Land-based Aerobic Trials?

Physical function/fitness

effect size=0.65 (sustained at follow up)

What doesn’t improve?

Sleep effect size=0.01 NS (NS at follow up)

What isn’t sustained?

Pain effect size=0.31 (0.13 NS at follow up)

Hauser, 2010, Arthritis Rsch & Ther

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Mindful movement interventions:

What is Emerging in FM for Pain & Sleep?

Tai chi (land or water)

QigongYoga w/ mindfulness

Mist , Firestone & Jones, 2013,J of Pain Rsch

Mindful Movement Hypothesis

Mindfulness entails meditation and other strategies for developing greater:

• Presence of mind in the present moment, acting with awareness

• Non-judgement / non-reactivity of symptoms

• Acceptance / willingness to learn from pain and other challenging experiences

When exercise is combined with mindfulness, can patients learn to move mindfully and better accept disagreeable sensations arising during movement? Moreover does improved acceptance modulate pain by psycho-physiological mechanisms such as activation of the PAG?

The raisins sitting in my sweaty palm are getting stickier by the minute. They don't look particularly appealing, but when instructed by my teacher, I take one in my fingers and examine it.

Time Magazine, February 2, 2014

The ability to focus for a few minutes on a single raisin isn't silly if the skills it requires are the keys to surviving and succeeding in the 21st century

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Conclusion: Eight weeks of daily yogic meditation reversed the pattern of increased expression of genes associated with inflammation

Science Meets Meditation

Epigenetics:Changes in gene

expression related to environmental

factors

State of Published Evidence in FM

�Meditation

�Mostly focuses on mindfulness (6 MBSR studies)

�Improves quality of life, mood

�Mixed results in symptom severity but generally not pain reduction

�Mind + Body Movement is different exercise or meditation alone

1 Mist SD, Firestone KA, Jones KD 2013

Cognitive Behavioral Therapy: Meta analysis

• Reduced depressed mood; small effect (p=0.004)

• Improved pain self efficacy; large effect (p=0.003)

• Operant behavioral therapy reduced the number of physician visits; large effect (p<0.001)

• No significant effect on pain (p=0.28), fatigue (p=0.61), sleep (p=0.50), health related quality of life (p=0.37)

• iPhone app

(Bernardy, et al., 2010, J Rheumatology)

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Acupuncture

AcupunctureA 5000-year old medical system based on the theory that “Qi” (the life force which flows throughout our body) is out of balance

Deare, JC, et al. Acupuncture for treating fibromyalgia. Cochrane database review. 2013, May 31

1. There is low to moderate-level evidence that acup uncture improves pain and stiffness

2. The effect lasts up to one month

Reviewed 9 randomized controlled studies (i.e. sham acupuncture) involving 321 subjects:

Cochrane Database Review 2013

3. Electro acupuncture is probably more effective th an manual acupuncture

4. The effect of acupuncture does not consistently d iffer from sham acupuncture in reducing pain or fatigue

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International Perspective

Great Britain, Germany, Canada and Israel all include acupuncture among the highest level of evidence and suggest it be used depending on the individual’s interest.

State of Published Evidence: Herbal

Medicine

� Huge field with very little research

� Several Chinese medicine formulas have been evaluat ed but study quality is low and none have been replica ted

� Topical capsaicin has been shown to improve sleepdisturbances and tenderness but not pain.

State of the Current Evidence: Diet

�Generally poor evidence in chronic pain due to lack of studies

�Five studies of fibromyalgia patients without additional diseases

�Holton, et al at OHSU found that MSG worsened fibromyalgia severity in patients with FM & IBS

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Raw Foods Diet

Kindler, L.L., Jones, K.D., & Holton, K. (2012). Potential dietary links for central sensitization in fibromyalgia: past reports, future directions. Clinical Rheumatology

Optimal Nutrition

• Nutrition is argued to be the single most important factor in optimizing your patient’s health

• Positive vs. negative aspects to diet:

• Positive� Vitamins, Minerals, Protein, EFAs, Fiber

• Negative� Food additives, excess sugar, pesticides, herbicides,

trans fats

Food Additives

• Excitotoxins

� Glutamate, aspartate and L-cysteine

� Found under a myriad of names

• Artificial sweeteners

� Aspartame, acesulfame K, saccharin, sucralose

Artificial colors

� Interactions w/excitotoxins

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Glutamate

• Glutamate – a non-essential, negatively charged AA from diet

• The most ubiquitous excitatory neurotransmitter in mammals

– Functions all over body (gut, immune system, pancreas, neuromuscular junction and brain)

– Precursor to the inhibitory neurotransmitter GABA

• Disordered glutamatergic neurotransmission has been implicated in chronic pain

• Excess glutamate can lead to excitotoxicity

• Bound vs free glutamate

– Meat versus soy sauce

Food Additives

Gelatin

Focus on REAL Food

• Real Food – Food that is not highly processed

� Low in additives, no trans fats

� High in nutrients

� High in fiber

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What Nutritional Factors are Important for Optimal Glutamatergic Function?

� Adequate protein and low sugar

� Antioxidants - Vitamins C & E

� Vitamin D

� Omega-3 Fatty Acids

� Magnesium

� Zinc

Hidden ExcitotoxinsAcesulfame-K (Sunett, Sweet One)Aspartame (Equal, NutraSweet, Canderel)Autolyzed yeast (or autolyzed yeast extract)Barley malt extractBouillonBrothCalcium caseinateCarrageenanFlavoringGelatinHydrolyzed corn, wheat, or soy protein L-cysteineMalt extractMalt flavoringModified food starch (any type)Monopotassium glutamateMonosodium glutamate (MSG)

Natural flavoringNutritional yeastPlant protein extract Saccharin (Sweet ’N Low)SeasoningSmoke flavoringSodium benzoateSodium caseinateSodium guanylateSodium inosinateSoy (soybean oil /soy lecithin are OK to eat)Soy protein concentrateSoy protein isolateSpices (this term can hide other ingredients)StockSucralose (Splenda)Textured proteinWhey protein concentrateWhey protein isolateYeast extract

Too Confusing?:

Fooducate iPhone app

Complementary & Alternative Evidence

Langhorst et al. (2012) Complementary and alternative therapies for fibromyalgia syndrome. Systematic review, meta-analysis and guideline. Schmerz, 26(3):311-7.

Qigong, Tai Chi, Yoga w/mindfulness - Strong evidenc e

Hydrotherapy - Strong evidence

Acupuncture – mixed evidence

Manual Therapies- mixed evidence

Relaxation, Biofeedback, Mindfulness – mixed evidenc e

Herbs, nutraceuticals, reiki, homeopathy – not recom mended

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Summary: Practice Points

Chronic pain is common and characterized by:

– Widespread pain in peripheral tissues

– Psychological distress (at least initially)

– Central sensitization

– Physical Deconditioning

Pain component is consequence of disordered neurophysiology:

– Patients perceive more pain from non-painful stimuli than do healthy controls and experience greater pain from painful stimuli

Rationale for treatment involves 4 important strategies:

– Reduction of peripheral nociceptive input

– Improvement or prevention of central sensitization

– Treatment of pain-related negative affect

– Enlisting the patient as a partner (education, exercise, diet, CBT)

Jones, K.D. & Paiva, E. (2011) Developing an inter disciplinary fibromyalgia clinical practice.Best Practices Rheum.

The EndQ & A