Polypharmacy as a rational treatment approach for chronic pain

1
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_at_mail.med.upenn.edu

2
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

3
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.
  20041531-46.
• Sindrup SH, Jensen TS. Pain. 199983389-400.
• Galer BS. Neurology. 199545(12 suppl 9)S17-S25.

4
Medication selection in pain is based upon
more than just pain severity

• Ease of use
• Dosing simplicity
• Titration simplicity
• Patient competence and convenience
• Pains 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. 199983389-400.
• Galer BS. Neurology. 199545(12 suppl 9)S17-S25.
• Gallagher RM, Verma S. Sem Neurosurg.
  20041531-46.

5
Public Health ChallengeHow do we prevent
injuries from causing chronic pain?

• Injuries gtgt nerve damage gtgt pain gtgtacute distress
• continued nociception gtgt spinal cord damage
• gtgt fear, distress gtgtgt brain damage gtgt
• gtgt chronic pain disease

6
ANS activation ltltlt Stress ltltlt Pain ltltlt
BRAIN PROCESSING
Spinal cord Damage
Nerve injury

C fiber
Abeta fiber
Limb trauma
Adapted from Woolf Mannion, Lancet 1999 Attal
Bouhassira, Acta Neurol Scand 1999
7
THE END CPRS Pain Cycle

• Pathology
• Muscle atrophy,
• weakness
• Bone
• demineralization
• -Depression

• Pathophysiology of Maintenance
• Radiculopathy
• Neuroma traction
• Myofascial sensitization

Acute injury and pain

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

Central sensitization
Disability
Less active Kinesophobia Decreased
motivation Increased isolation Role loss
Peripheral Sensitization Na channels Lower
threshold
Neurogenic Inflammation - Glial activation -
Pro-inflammatory cytokines - blood-nerve
barrier dysruption
8
Challenges of OEF/OIF Veteran Cohort

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

9
Does early intervention make a difference?
Castillo et al. Pain 124 (2006) 321-329

• 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

10
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.

11
Gabapentin in the Treatment of Postherpetic
Neuralgia
100
Placebo (n116)
Gabapentin (n109)
80
plt.001
59.5
60
43.2
of Patients
40
22.9
17.4
20
12.1
8.6
7.8
2.8
0
Moderately orMuch Improved
MinimallyImproved
No Change
Worse
Adapted from Rowbotham M, et al. JAMA.
1998280(21)1837-1842.
12
What happens above the spinal cord?
13
Pain is conditionableExpectation of Pain
Activates the Anterior Cingular Gyrus
Can we measure the impact of experience?
Sawamoto et al. J Neurosci. 2000207438.
14
Serotonin and Norepinephrine inDepression and
Pain
PAIN and EMOTION
PrefrontalCortex - anterior cingulate
Limbic System
Serotonin Pathways
Locus Ceruleus
Raphe
Norepinephrine Pathways
Verma S, Gallagher RM. Int Rev Psychiatry.
200012(2)103-114.Blier P, Abbott FV. J
Psychiatry Neurosci. 200126(1)37-43.
15
DIAGNOSIS There Are Many Painful Diseases and
Pain Diseases
Inflammatory / Immunological Mediation
Nociceptive pain Caused by activity inneural
pathways inresponse to potentiallytissue-damagin
g stimuli
Neuropathic pain Initiated or caused by a
primary lesion or dysfunction in the nervous
system
CANCER PAIN, LBP, CHRONIC FACIAL PAIN (mixed
pain states)
Peripheralneuropathy
SENSITIZATION
CRPS
Postoperativepain
Arthritis
Postherpeticneuralgia
Trigeminalneuralgia
Sickle cellcrisis
Mechanicallow back pain
Neuropathic low back pain
Central post-stroke pain
Diabeticneuropathy
Sports/Exerciseinjuries
Phantom tooth pain
Complex regional pain syndrome.
16
Recognizing Neuropathic Pain
Common signs and symptoms

• Persistent burning sensation
• Paroxysmal lancinating pains
• Paresthesias
• Dysesthesias
• Hyperalgesias
• Allodynias

Galer BS. Neurology. 199545(suppl 9)S17-S25
Backonja M-M et al. Neurol Clin.199816775-789.
17
Pain Drawing Neuropathy Types
Boulton AJM et al. Med Clin North Am.
199882909-929 Portenoy RK. Pain Management
Theory and Practice. 1996108-113 Katz N. Clin
J Pain. 200016S41-S48
18
Numerical Rating Scale Monitoring Patient
Progress
Severe Cant function
Moderate Bothersome
Excruciating, ER time
Mild, in background
Burning at the stake !!
Just Noticeable
No pain
Worst possible pain

• 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

Adapted from Farrar JT et al. Pain.
200194149-158.
19
Efficacy Medication Trials

• Disease specific
• vs
• Mechanism specific

20
Effect of Medications on Pain in a Preclinical
Model of Persistent Neuropathic Pain
Late-Phase Pain Behavior in Formalin Model
Vehicle control
Duloxetine
100
Venlafaxine
Gabapentin

Amitriptyline
75

plt.05 vs vehicle

Total Paw-Licking Time (Late Phase)( of Control)
50






25

0
0.1
1
10
100
Drug (ip, -30 Minutes, mg/kg, N6-8)
Simmons/Iyengar. Data on file, Eli Lilly and
Company. This information concerns a use that has
not been approved by the US FDA.
21
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

22
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

23
Other NP agents

• Voltage gated Calcium channels
• Gabapentin Every 3-5 days
• 0 0 300 mg
• 300 0 300 mg
• 300 300 300 mg
• 300 300 600 mg
• 600 300 600 mg
• 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

24
Other NP agents

• Serotonin Norepinephrine Reuptake Inhibitors
  (SNRIs) for diabetic neuropathy
• Duloxetine
• 20 mg or 30 mg in AM
• In 1- 2 weeks, if tolerated, increase to 40 60
  mg in AM
• Target dose 60 mg for 3 weeks.
• 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

25
Efficacy Comparison, Neuropathic Pain
Number-Needed-to-Treat Analyses
4.4
Lidocaine Patch 5 (Meier et al, 2003)
2.7
Opioids (Raja et al, 2002)
4.0
Tricyclic Antidepressants (Raja et al, 2002)
Drug or Therapeutic Class
3.2
Gabapentin (Rowbotham et al, 1998)
5.0
Gabapentin (Rice and Maton, 2001)
5.3
Capsaicin (Sindrup and Jensen, 1999)
8
15
20
10
0
5
Number-needed-to-treat (NNT) Mean 95 Cl
Meier et al. Pain. 2003106151158.
26
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?

27
Lidocaine Patch 5in Postherpetic Neuralgia
5
Observational only
0
Vehicle
Change in VAS (mm)
-5


-10
Active









N35


-15
0.5
2
4
6
9
12
Postapplication Time (Hours)
VASvisual analog scale.P.0001 to P.021,
active vs observational only. P.016 and
P.041, vehicle vs observational only. Plt.001
to P.038, active vs vehicle from 4 to 12 hours.
Adapted from Rowbotham MC et al. Pain.
19966539-44.
28
Efficacy of Controlled-Release Oxycodone in
Postherpetic Neuralgia (N50)
Placebo
N50
60
55
Oxycodone CR
50
p.0001p.0004
50
42

40

34
32
VAS Pain Intensity(0-100 mm)

30
22
20
10
0
Steady Pain
Brief Pain
Allodynia
Adapted from Watson CP, Babul N. Neurology.
199850(6)1837-1841.
29
Analgesic Therapy in PHN A Quantitative
Systematic Review

• Summary based on 56 blinded RCTs

Number Needed to Treat
Hempenstall K et al. PLoS Med. 20052628-644.
30
Efficacy Comparison, Neuropathic Pain
Number-Needed-to-Treat Analyses
4.4
Lidocaine Patch 5 (Meier et al, 2003)
2.7
Opioids (Raja et al, 2002)
4.0
Tricyclic Antidepressants (Raja et al, 2002)
Drug or Therapeutic Class
3.2
Gabapentin (Rowbotham et al, 1998)
5.0
Gabapentin (Rice and Maton, 2001)
5.3
Capsaicin (Sindrup and Jensen, 1999)
8
15
20
10
0
5
Number-needed-to-treat (NNT) Mean 95 Cl
Meier et al. Pain. 2003106151158.
31
Amitriptyline in SCI pain

• Cardenas DD et al. Pain. 200296365-373.
• Sample 84 patients with SCI and chronic pain
• Design Double-blind, RCT with amitriptyline
• vs. 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

32
Nortriptyline vs Placebo in Chemotherapy-induced
Painful Paresthesias

• Hammack JE et al. Pain. 200298195-203.
• 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

33
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, 611 113-120, 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 83183-192, 1999

34
Depression and Pain Comorbidity
Pain, A condition or symptom that causes or
activates depression
Pain
Remission
Recovery
Response
Relapse
Recurrence
Relapse
Normalcy
Progression to disorder
Depression Symptoms
DEPRESSIVE ILLNESS
Continuation
Acute
Treatment Phases
Maintenance
Kupfer DJ. Depression. J Clin Psychiatry.
199152(suppl)28-34. Dohrenwend BP, et al.
Facial Pain and depression. Pain.
199983(2)183-192. Gallagher Verma, Pain and
depression. Prog Pain Res Man 2004 Raphael et
al, Fibromyalgia. Pain 2004
35
CHOOSING MEDICATION

• Expect partial effects use multiple agents with
  different mechanisms
• from different classes
• from the same class

36
Target keeping pain below 5 to enable quality
of life
Severe Cant function
Moderate Bothersome
Excruciating, ER time
Mild, in background
Burning at the stake !!
Just Noticeable
No pain
Worst possible pain

• 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

Adapted from Farrar JT et al. Pain.
200194149-158.
37
Algorithm for Medication Selection in Chronic
Pain With and Without Comorbid Depression
Neuropathicpain
Nociceptivepain
Pain condition depression
Secondary depression
Primary D.
Secondary sleepdisturbance
Evaluate risks
Persists afteradequateanalgesia
Evaluate risks
Persists afteradequateanalgesia
NSAIDs,Cox-IIs,opioids, lidocaine p.? doxepin
cr.?
SSRI trial
Evaluate risks
Evaluate risks
Lidocaine patchgabapentin other AED (Ca
Na channels) alpha 2 agonists
(tizanidine, clonidine)opioids
SNRIs venlafaxine, duloxetine
Antihistamine,zolpidem,etc.
Trazodone Low-doseTCA
Titrate TCAs (Na channels and SNRI)
desipramine, nortriptyline,
Adapted from Gallagher RM, Verma S. Semin Clin
Neurosurgery. 2004. This information concerns
uses that have not been approved by the US FDA.
38
Prioritized Problem List And Goal-oriented
Management PlanOsteoarthritis, spinal stenosis
in 60-year-old executive/grandmother
Immediate Problems Goal Statement Plan
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 gtgt 2400 mg Nortriptyline 10 gt 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
39
Prioritized Problem List And Goal-oriented
Management PlanOsteoarthritis, spinal stenosis
in 60-year-old executive/grandmother
Pivotal Problems Goal Statement Plan
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
40
Prioritized Problem List And Goal-oriented
Management PlanOsteoarthritis, spinal stenosis
in 60-year-old executive/grandmother
Background Problems Goal Statement Plan
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
41
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.

42
Final Thoughts

• Success in rational polypharmacy requires
• Establish appropriate goalspain 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

43
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.