polypharmacy as a rational treatment approach for chronic pain rollin m. gallagher, md, mph...
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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: [email protected]
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.