Polypharmacy as a rational treatment approach for chronic pain

Rollin M. Gallagher, MD, MPH

University of Pennsylvania School of Medicine

Philadelphia Veterans Medical Center

Email: rgallagh@mail.med.upenn.edu

Goals of This Presentation

1) To review mechanisms of acute pain and chronic pain diseases and conditions

2) To discuss the rational use of polypharmacy and integrated multi-modality treatment for chronic pain

Medication selection in pain is based upon more than just pain severity

• Diagnosis

• Mechanisms of pain(s)

• Efficacy– Clinical trial data

• Comorbidities: medical and psychiatric

• Prior treatment responses

• Side-effect burden, toxicity risk, drug and disease interactions

• Gallagher RM, Verma S. Sem Neurosurg. 2004;15:31-46.• Sindrup SH, Jensen TS. Pain. 1999;83:389-400.• Galer BS. Neurology. 1995;45(12 suppl 9):S17-S25.

Medication selection in pain is based upon more than just pain severity

• Ease of use– Dosing simplicity– Titration simplicity– Patient competence and convenience

• Pain’s psychosocial context and the doctor-patient relationship:- stigma- cost- illness behavior- risk of treatment non-adherence- risk of medication misuse

• Sindrup SH, Jensen TS. Pain. 1999;83:389-400.• Galer BS. Neurology. 1995;45(12 suppl 9):S17-S25.• Gallagher RM, Verma S. Sem Neurosurg. 2004;15:31-46.

Public Health ChallengeHow do we prevent injuries from

causing chronic pain?

Injuries >> nerve damage >> pain >>acute distress

continued nociception >> spinal cord damage

>> fear, distress >>> brain damage >>

>> chronic pain disease

C fiber

Abeta fiber

Nerve injury

PhenotypicalChanges

Spinal cord Damage

Neuro-plasticity

Central sensitization

Alteration of modulatory

systems

Ectopic discharge

Ectopic discharge

Adapted from Woolf & Mannion, Lancet 1999Attal & Bouhassira, Acta Neurol Scand 1999

ANS activation <<< Stress <<< Pain <<< BRAIN PROCESSING

+++

Limb trauma

THE END: CPRS Pain CyclePathology:-Muscle atrophy, weakness;-Bone demineralization;-Depression

Less activeKinesophobiaDecreased motivationIncreased isolationRole loss

Disability

Pathophysiology of Maintenance:-Radiculopathy-Neuroma traction-Myofascial sensitization

Psychopathology of maintenance:-Encoded anxiety dysregulation - PTSD-Emotional allodynia and mood disorder

NeurogenicInflammation:- Glial activation- Pro-inflammatory cytokines- blood-nerve barrier dysruption

Acute injuryand pain

PeripheralSensitization:Na+ channelsLower threshold

Central sensitization

Challenges of OEF/OIF Veteran

Cohort

Recent evidence suggests that access to pain treatment after severe limb trauma leads to better outcomes.

567 severe single extremity trauma patients at 7 years

• Predictors of poor outcome before injury include:• Alcohol abuse 1 month before injury • Older age, lower education, low self efficacy (Gallagher Pain 1989)

• Predictors of poor outcome at 3 months post-injury:• Acute pain intensity, anxiety, depression and sleep disturbance

Does early intervention make a difference?

Castillo et al. Pain 124 (2006): 321-329

Opioid protective effect

“Patients treated with narcotic medication for pain at three months post-discharge were protected against chronic pain, despite the fact that these patients had higher pain intensity levels and were thus at higher risk.”

“The results presented here appear to lend support to the theory that…

..early aggressive pain treatment may protect patients from central sensitization and chronic pain.”

Gabapentin in the Treatment of Postherpetic Neuralgia

12.1% 7.8%

59.5%

8.6%

43.2%

17.4%

2.8%

22.9%

0

20

40

60

80

100

Moderately orMuch Improved

MinimallyImproved

No Change Worse

% o

f Pat

ient

s

Placebo (n=116)Gabapentin (n=109)

p<.001

Adapted from: Rowbotham M, et al. JAMA. 1998;280(21):1837-1842.

What happens above the spinal cord?

Pain is conditionable:Expectation of Pain Activates the

Anterior Cingular Gyrus

Sawamoto et al. J Neurosci. 2000;20:7438.

Can we measure the impact of experience?

Serotonin and Norepinephrine inDepression and Pain

Verma S, Gallagher RM. Int Rev Psychiatry. 2000;12(2):103-114.Blier P, Abbott FV. J Psychiatry Neurosci. 2001;26(1):37-43.

Serotonin Pathways

Norepinephrine Pathways

Limbic System

PrefrontalCortex

- anterior cingulate

Raphe

Locus Ceruleus

PAIN and EMOTION

Neuropathic low back pain

DIAGNOSIS There Are Many Painful Diseases and Pain Diseases

*Complex regional pain syndrome.

Nociceptive painCaused by activity inneural pathways in

response to potentiallytissue-damaging stimuli

Neuropathic painInitiated or caused by a

primary lesion or dysfunction

in the nervous system

Postoperativepain

Mechanicallow back pain

Sickle cellcrisis

Arthritis

Peripheralneuropathy

Postherpeticneuralgia

Diabeticneuropathy

Sports/Exerciseinjuries

Central post-stroke pain

Trigeminalneuralgia

Inflammatory / Immunological Mediation

CANCER PAIN, LBP, CHRONIC FACIAL PAIN

(mixed pain states)

SENSITIZATION CRPS*

Phantom tooth pain

Recognizing Neuropathic Pain

• Persistent burning sensation

• Paroxysmal lancinating pains

• Paresthesias

• Dysesthesias

• Hyperalgesias

• Allodynias

Common signs and symptoms

Galer BS. Neurology. 1995;45(suppl 9):S17-S25; Backonja M-M et al. Neurol Clin.1998;16:775-789.

Pain Drawing & Neuropathy Types

Boulton AJM et al. Med Clin North Am. 1998;82:909-929; Portenoy RK. Pain Management: Theory and Practice. 1996:108-113; Katz N. Clin J Pain. 2000;16:S41-S48

Numerical Rating Scale: Monitoring Patient Progress

• Improvement can be monitored

• Gives clinician and patient a consistent understandable measure with intra-rater reliability that facilitates discussion regarding: changes in pain, response to treatment

• Reduction of 2 points represents a clinically important

0000 1111 2222 3333 4444 5555 6666 7777 8888 9999 10101010No pain

Worst possible pain

Adapted from Farrar JT et al. Pain. 2001;94:149-158.

SevereCan’t

function

Excruciating, ER time

ModerateBothersome

Mild, in backgroundJust

NoticeableBurning at the stake !!

Efficacy – Medication Trials

Disease specific

vs

Mechanism specific

Simmons/Iyengar. Data on file, Eli Lilly and Company.This information concerns a use that has not been approved by the US FDA.

Effect of Medications on Pain in a Preclinical Model of Persistent Neuropathic Pain

Drug (ip, -30 Minutes, mg/kg, N=6-8)0.1 1 10 100

0

25

50

75

100 DuloxetineVenlafaxine Gabapentin Amitriptyline

Vehicle control

*

*

*

*

*

**

*

*

*

Tota

l Paw

-Lic

king

Tim

e (L

ate

Phas

e)(%

of C

ontr

ol)

Late-Phase Pain Behavior in Formalin Model

*p<.05 vs vehicle

Efficacy in Neuropathic Pain• Agents with consistent efficacy demonstrated in

randomized, controlled trials for neuropathic pain– Lidocaine Patch 5%* (topical analgesic)

– Anticonvulsants: gabapentin,* valproate, carbamazepine

– Pregabalin

– Tricyclics: nortriptyline,† desipramine,† amitriptyline

– SNRIs: venlafaxine,† duloxetine*

– Opioids: oxycodone,† tramadol†

– GABA B agonist: baclofen†

* FDA approved for the treatment of neuropathic pain† Not approved by FDA for this use

Tricyclic Antidepressants

• Multiple mechanisms (Na+ channels, 5-HT & NE reuptake blockade)

• RCTs in diabetic peripheral neuropathy (DPN) and postherpetic neuralgia

• Dosing: Initiate dose at 10 mg hs to 25 mg hs and ↑ as tolerated to 10 mg to 50 mg– If no effect at 2 weeks, continue to ↑ to ≥150 mg if

needed

• Documented, but limited, efficacy for fibromyalgia and chronic low back pain

Other NP agents

Voltage gated Calcium channels:1) Gabapentin: Every 3-5 days

1) 0 0 300 mg 2) 300 0 300 mg3) 300 300 300 mg4) 300 300 600 mg5) 600 300 600 mg6) 600 600 600 mg

• Pregabalin: Every 1-2 weeks as tolerated• 50 mg TID or 75 mg BID • 100 mg TID or 150 mg BID

Other NP agentsSerotonin – Norepinephrine Reuptake Inhibitors (SNRIs)

for diabetic neuropathy

1) Duloxetine 1. 20 mg or 30 mg in AM2. In 1- 2 weeks, if tolerated, increase to 40 – 60 mg in AM3. Target dose 60 mg for 3 weeks.4. Maximum dose 120 mg

2) Venlafaxine (Effexor) LA (check BP) 1. 137.5 mg in AM for 5 days, then increase by 37.5 mg

every 5 days until 150 mg for 3 weeks 2. Increase after 2 weeks to 225 mg . 3. Increase after 2 weeks to 300 mg

Efficacy Comparison, Neuropathic Pain: Number-Needed-to-Treat Analyses

Capsaicin(Sindrup and Jensen, 1999)

Gabapentin(Rice and Maton, 2001)

Tricyclic Antidepressants

(Raja et al, 2002)

Opioids(Raja et al, 2002)

Lidocaine Patch 5%

(Meier et al, 2003)

Gabapentin(Rowbotham et al, 1998)

Dru

g o

r Th

era

peu

tic C

lass

Number-needed-to-treat (NNT)Mean ±95% Cl

0 5 10 15 20

5.3

5.0

3.2

4.0

2.7

4.4

Meier et al. Pain. 2003;106:151–158.

∞

Evidence for Disease Specificity in Efficacy Trials for NP Pain

EFFICACY:

SPECIFIC FOR DISEASE? - Postherpetic neuralgia- Spinal cord injury pain- Painful HIV neuropathy- Chemotherapy neuropathy- Diabetic neuropathy- Phantom tooth pain?

GENERALIZED TO NEUROPATHIC MECHANISM?

*

Lidocaine Patch 5%in Postherpetic Neuralgia

Observational only

Vehicle

Active

Postapplication Time (Hours)0.5 2 4 6 9 12

-15

-10

-5

0

5

* **

VAS=visual analog scale.*P=.0001 to P=.021, active vs observational only. **P=.016 and P=.041, vehicle vs observational only. † P<.001 to P=.038, active vs vehicle from 4 to 12 hours.

Adapted from: Rowbotham MC et al. Pain. 1996;65:39-44.

****

* * *

† ††

†

Cha

nge

in V

AS

(mm

)

N=35

Analgesic Therapy in PHN: A Quantitative Systematic Review

Summary based on 56 blinded RCTs:

Hempenstall K et al. PLoS Med. 2005;2:628-644.Hempenstall K et al. PLoS Med. 2005;2:628-644.

4.93

4.76

4.39

3.26

2.67

2.64

2.00

0 2 4 6

Pregabalin

Tramadol

Gabapentin

Capsaicin

Opioids

TCAs

Lidocaine Patch 5%

Number Needed to Treat

Efficacy Comparison, Neuropathic Pain: Number-Needed-to-Treat Analyses

Capsaicin(Sindrup and Jensen, 1999)

Gabapentin(Rice and Maton, 2001)

Tricyclic Antidepressants

(Raja et al, 2002)

Opioids(Raja et al, 2002)

Lidocaine Patch 5%

(Meier et al, 2003)

Gabapentin(Rowbotham et al, 1998)

Dru

g o

r Th

era

peu

tic C

lass

Number-needed-to-treat (NNT)Mean ±95% Cl

0 5 10 15 20

5.3

5.0

3.2

4.0

2.7

4.4

Meier et al. Pain. 2003;106:151–158.

∞

Amitriptyline in SCI pain

Cardenas DD et al. Pain. 2002;96:365-373.

• Sample: 84 patients with SCI and chronic pain

• Design: Double-blind, RCT with amitriptylinevs. active placebo, benztropine

• Results: – No significant differences were found among the groups in pain intensity

or pain-related disability.– The findings do not support the routine

use of amitriptyline in the treatment of chronic

pain in patients suffering from SCI

Nortriptyline vs Placebo in Chemotherapy-induced Painful Paresthesias

Hammack JE et al. Pain. 2002;98:195-203.

• Sample: 51 patients with painful paresthesias from chemotherapy -induced neuropathy

• Design: 4-week, double-blind, RCT with cross-over after 1-week washout

• Dose: Target dose = 100 mg/day

• Outcome: – no differences in pain intensity or quality of life, slight improvement in sleep on NT– SE burden higher on NT

• Conclusion:NT provides modest improvement, at best, in chemotherapy- induced painful paresthesias

Chronic facial pain and depression

Gallagher, R.M., Marbach, J., Raphael, K., Dohrenwend, B., Cloitre, M.: Is there co-morbidity between temporomandibular pain dysfunction syndrome and depression?: A pilot study. Clinical Journal of Pain, 7: 219-225, 1991

Gallagher, R.M., Marbach, J., Raphael, K., Handte, J., Dohrenwend, B.: Seasonal Variation in chronic TMPDS Pain and Mood Intensity Pain, 61[1]: 113-120, 1995.

Dohrenwend, B., Marbach, J. , Raphael, K., Gallagher, R.M.: Why is depression co-morbid with chronic facial pain? A family study test of alternative hypotheses. Pain 83:183-192, 1999

Depression and Pain Comorbidity

ResponseRemission

Depression Symptoms

DEPRESSIVE ILLNESS

Recovery

ContinuationAcute

Relapse

Kupfer DJ. Depression. J Clin Psychiatry. 1991;52(suppl):28-34. Dohrenwend BP, et al. Facial Pain and depression. Pain. 1999;83(2):183-192. Gallagher & Verma, Pain and depression. Prog Pain Res Man 2004Raphael et al, Fibromyalgia. Pain 2004

Treatment Phases

“Normalcy”

Maintenance

Relapse RecurrenceProgression

to disorder

Pain

Pain, A condition or symptom that causes or activates depression

CHOOSING MEDICATION

Expect partial effects: use multiple agents with different mechanisms: – from different classes

– from the same class

Target – keeping pain below 5 to enable quality of life

• Improvement can be monitored

• Gives clinician and patient a consistent understandable measure with intra-rater reliability that facilitates discussion regarding: changes in pain, response to treatment

• Reduction of 2 points is clinically meaningful

0000 1111 2222 3333 4444 5555 6666 7777 8888 9999 10101010No pain

Worst possible pain

Adapted from Farrar JT et al. Pain. 2001;94:149-158.

SevereCan’t

function

Excruciating, ER time

ModerateBothersome

Mild, in backgroundJust

NoticeableBurning at the stake !!

Nociceptivepain

Neuropathicpain

Pain condition +

depressionSecondary sleep

disturbance

Secondary depression Primary D.

NSAIDs,Cox-IIs,opioids,

lidocaine p.? doxepin cr.?

Persists afteradequateanalgesia

Persists afteradequateanalgesia

Evaluate risks

Evaluate risks

Antihistamine,zolpidem,

etc.

Trazodone

Low-doseTCA

Lidocaine patch;gabapentin & other

AED (Ca+ & Na+ channels); alpha 2 agonists

(tizanidine, clonidine);opioids

Titrate TCAs (Na+ channels and SNRI) :

desipramine, nortriptyline,

SSRI trial

Evaluate risksSNRIs: venlafaxine,

duloxetine

Algorithm for Medication Selection in Chronic Pain With and Without Comorbid Depression

Adapted from Gallagher RM, Verma S. Semin Clin Neurosurgery. 2004.This information concerns uses that have not been approved by the US FDA.

Evaluate risks

Prioritized Problem List And Goal-oriented Management PlanOsteoarthritis, spinal stenosis in 60-year-old executive/grandmother

Pain from osteoarthritis knees and spine

Obtain pain control Opioid titration (LA oxycodone and Percocet® for BtP), Lidocaine 5% patches

Radicular pain from spinal stenosis

Obtain pain control Nerve root block trials. Gabapentin >> 2400 mg; Nortriptyline 10 > 20 mg

Threatened job loss

Obtain medical leave to buy time for functional capacity evaluation and pain control

Crisis counseling for medical leave and to retain benefits

Immediate Problems Goal Statement Plan

Prioritized Problem List And Goal-oriented Management PlanOsteoarthritis, spinal stenosis in 60-year-old executive/grandmother

Myofascial pain, deconditioning

Improve posture and recondition spine muscles

Physical rehabilitation program

Trigger-point therapy tizanidine 4mg

Osteoarthritis with gait disturbance

Reduce weight, retrain gait, recondition muscles

Rofecoxib

Rehabilitation program with gait training, exercise program and weight loss

Depression with neurovegetative impairments

Achieve remission of symptoms and impairments

Pain control

Sertraline 100 mg

Pivotal Problems Goal Statement Plan

Prioritized Problem List And Goal-oriented Management PlanOsteoarthritis, spinal stenosis in 60-year-old executive/grandmother

Adjustment to functional and social losses

Facilitate job change and “readiness for change”

Establish functional capacity for occu-pational change

Focal psychotherapy

Loss of family role Restore meaningful role in family

Family therapy for acceptance of disease, treatment plan (eg, opioids) and role change

Background Problems Goal Statement Plan

Final Thoughts

• A medication that is effective in one neuropathic pain disorder may not be effective in others. But it may be, so try it.

• Mechanisms of neuropathic pain may differ in different diseases and within diseases, accounting for variability in study results.

• Be aware of drug interactions in patients with several chronic conditions.

Final Thoughts

Success in rational polypharmacy requires:

• Establish appropriate goals—pain relief and quality of life

• Know mechanism and disease-specific data related to efficacy

• Present recommendations with confidence based upon evidence, not just charisma

• Establish patient and doctor responsibilities

Final Thoughts

Success in rational polypharmacy requires:

• Run sequential clinical trials of medications based on efficacy, SE burden and toxicity, comorbidities, ease of use, and patient adherence.

• If partial effects, maintain on minimal effective dose while pursuing additional medication trials, one at a time.

• Look for additive benefit of several medications, targeting different mechanisms, to obtain control of pain to improve quality of life.