Download Diabetic Peripheral Neuropathy Basics for Drug Selection

Diabetic Peripheral Neuropathy
Basics for Drug Selection
Dave Joffe, R.Ph, CDE, FACA
1
Dave Joffe, R.Ph, CDE, FACA
Conducted over 50 Diabetes Days at Eckerd, with
help from Bayer, MiniMed ,Novo, Lilly, Lifescan, and
Disetronic
Eckerd Patient Care Pharmacist 1999- 2000. Managed
Patients full time in 3 Retail Locations. Responsible for 170
Diabetes Patients with Full Therapy Rights on Over 70
Patients.
Pharmacist --Madeira Beach FL
President Insulin Pump Specialty Group AADE
Past -President JDRF Tampa Bay Chapter
Past President Florida West Coast Assoc. Diabetes Educators
Diabetes Outcome Manager, currently managing over 100 diabetes
patients in private practice, with primary care physicians. Certified Insulin
Pump trainer Deltec, Animas and Medtronic
Editor in Chief –Diabetes In Control .com
2
Poll
• Do patients ever come to you complaining of
intense burning or sharp pains in their feet?
3
1
Program Overview:
• This program focuses on information to help
pharmacists advise patients on DPN.
• We give you valuable information on current
methods of treatment and how these impact
DPN.
• Special emphasis is placed on improving
outcomes and giving you the knowledge to
advise patients and other diabetes medical
professionals on proper therapy choices and
reasons for medication selection
4
Objectives
At the end of this program the pharmacist
should be able to discuss:
• The Neural Systems and how
Neurotransmitters work
• The difference between Nociceptive and
Neuropathic Pain
• Signs and symptoms of Diabetic Peripheral
Neuropathy(DPN)
• Medical Management of DPN
• Advantage of newer medications for DPN
• Dosing recommendations, and Patient Safety
Issues.
5
The Nervous System
6
2
Neurons –Functional Systems
• Sensory or Afferent
•
− Collect info from organs or perception
− Sends info to the brain
Motor or Efferent
− Carry the signal from the brain and spinal cord
− Signal carries to the muscles, glands, blood vessels, organs
7
Neurotransmitters
Acetylcholine –
Transmits impulses
that signal muscles to
contract
Major Excitatory NT
Glutamate
–Major Inhibitory
NT’s
GABA and Glycine
8
Neurotransmission
9
3
Nociceptive vs Neuropathic Pain States
Nociceptive
• Pain that arises from a stimulus
•
•
Neuropathic
vs
that is outside of the nervous
system
Proportionate to the stimulation
of the receptor
When acute serves a protective
function
• Pain initiated or caused by a
•
•
•
primary lesion or dysfunction
in the nervous system
No nociceptive stimulation
required
Disproportionate to the
stimulation of receptor
Other evidence of nerve
damage
Serra J. Acta Neurol Scand. 1999;173(suppl):7-11.
10
Poll – True or False?
• An example of nociceptive pain would be
arthritis.
11
Examples of Nociceptive and
Neuropathic Pain
Nociceptive
Pain
Caused by activity in neural
pathways in response to
potentially tissue-damaging
stimuli
Arthritis
Postoperative
pain
Mechanical
low back pain
Sports/exercise
injuries
Mixed Type
Caused by a
combination of both
primary injury or
secondary effects
Neuropathic
Pain
Initiated or caused by
primary lesion or
dysfunction in the nervous
system
Central poststroke pain
Neuropathic low
back pain
Sickle cell
crisis
*Complex regional pain syndrome
CRPS*
Trigeminal
neuralgia
Postherpetic
neuralgia (PHN)
Distal
polyneuropathy
(eg, diabetic, HIV)
12
4
Stimulus-Evoked Symptoms
Symptom
Allodynia
Hyperalgesia
Hyperpathia
Definition
Painful response to a nonpainful stimulus
Heightened response to a
painful stimulus
Delayed, explosive pain to
a painful stimulus
Merskey H and Bogduk N. Classification of Chronic Pain. 1994.
13
Mechanisms – Neuropathic Pain
• Ectopic impulse generation
•
− Spontaneous neuronal firing
− Common mechanism for DPN
Peripheral/central sensitization
− Lowers activation thresholds of nociceptors and increases
firing rates
• Sympathetically maintained pain
− Nerves release NE which stimulates C nerve fibers which are
responsible for nociceptive input
14
Diabetic Peripheral Neuropathy (DPN):
What Is It?
• Nerve damage and dysfunction secondary to diabetes
mellitus type I or II
− Consensus definition1: “the presence of symptoms and/or
signs of peripheral nerve dysfunction in people with diabetes
after exclusion of other causes”
• A very common complication of diabetes
• A leading cause of neuropathic pain
1. Boulton AJ, et al. Diabet Med. 1998;15:508-514.
15
5
Diabetic Peripheral Neuropathy
16
Distal Symmetric Polyneuropathy
•
•
•
•
Most common form of DPN
Gradual onset
“glove-stocking” distribution
Acute or chronic
17
Open-Ended Question
Please use the chat window to respond.
• What do you recommend OTC for your
patients who complain of neuropathy?
18
6
Treatment of DPN: Satisfaction with
Medication is Inadequate
Patient Satisfaction With Prescription Medications
Extremely dissatisfied
5.1%
A little dissatisfied
7.5%
Somewhat satisfied
29.8%
Very satisfied
14.1%
Extremely satisfied
8.2%
NA
23.5%
0%
5%
10%
15%
20%
25%
30%
Percent of Patients
Few patients (22.3%) were extremely or very satisfied with
their prescription medications
Gore M, et al. Presented at: American Diabetes Association 64th Annual Scientific
Sessions; June 4, 2004; Orlando, Fla.
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Management of Neuropathic Pain
Associated With DPN and PHN
Pharmacotherapy
Neurostimulatory
Interventional
regional
anesthesia
Treatment approaches
Complementary/
alternative
Physical
rehabilitation
Psychological
Lifestyle
Belgrade MJ. Postgrad Med 1999;106:127-140
Orza et al. NeuroRehabilitation 2000;14:15-23
Ashburn and Staats. Lancet 1999;353:1865-1869
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Poll
• Do you recommend prescription therapy for
DPN to your patients who ask?
21
7
Management of Neuropathic Pain
Associated With DPN and PHN
• Gabapentin
• Opioids
• TCAs
• Cymbalta
• Topamax
• NSAIDs
• Carbamazepine
• Other AEDs
• All Others
46.6%
19.8%
12.9%
3.9%
1.6%
1.3%
1.2%
1.0%
11.7%
22
Clinical Management - Anticonvulsants
• Mechanisms of Action
− Block / modulate sodium, calcium channels
• Decrease action potential frequency
• Decrease excitation or decrease NT
release
− Increase GABA-ergic transmission
• Increase inhibition
− Decrease Glutamatergic transmission
• Decrease excitation
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Clinical Management –
Anticonvulsant agents
− First generation
• Carbamazepine
• Phenytoin
• Valproate
− Second generation
• Gabapentin* (Neurontin)
• Lamotrigine (Lamictal)
• Topiramate (Topamax)
• Pregabalin* (Lyrica)
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8
Clinical Management Anticonvulsant agents
• Gabapentin , Pregabalin
− Modulate the release of excitatory
neurotransmitters from the presynaptic cell
− MORE ON THIS LATER!
25
Pharmacological Options: Firstgeneration Anticonvulsants
• Phenytoin
− Mechanism unclear; may stabilize sodium channels1
− Effectiveness less clear than with carbamazepine
− May be limited by adverse effects and drug interactions
• Valproate
− Increases CNS GABA concentrations1
− Limited evidence of efficacy in DPN2
− Generally well tolerated1
• Carbamazepine
•
•
•
•
Inhibits sodium channels
Inhibits calcium channels
Blocks NMDA glutamate receptors
Increases extracellular serotonin levels
1. Physician’s Desk Reference. Montvale, NJ: Thomson PDR; 2004.
2. Kochar DK, et al. Acta Neurol Scand. 2002;106:248-252.
3.Engel J, Pedley TA, eds. Epilepsy: A Comprehensive Textbook. Philadelphia:
Lippincott-Raven; 1997.
.
26
Carbamazepine: Efficacy
• Indicated for trigeminal neuralgia1
• Significant pain relief compared with placebo shown in
DPN trials2-3
− 4-week double blind cross-over (N=40)2
− 6-week double blind cross-over (N=30)3
Safety and Tolerability
Black box warning for aplastic anemia and agranulocytosis1
Rare hypersensitivity reactions
Hyponatremia
Most frequent adverse events
Dizziness
Drowsiness
Unsteadiness
Nausea/vomiting
1. Tegretol [prescribing information]. East Hanover, NJ: Novartis; 2003.
2. Wilton TD. S Afr Med J. 1974;48:869-872.
3. Rull JA, et al. Diabetologia. 1969;5:215-218.
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9
Carbamazepine: Dosing
Recommendations
• Beginning dosage: 200 mg/d (2 divided doses)
• Titration: 100-mg increments every 12 hours
• Maximum dosage: 1200 mg/d
Tegretol [prescribing information]. East Hanover, NJ: Novartis; 2003.
28
Pharmacological Options: Second
Generation Anticonvulsants
• Lamotrigine
− Interacts with sodium channels and inhibits glutamate release1
− Limited evidence of efficacy in DPN2 and PHN
− Published data in other neuropathic pain states (ie, HIV3,4 and
trigeminal neuralgia5)
• Gabapentin
−
−
−
−
α 2 δ ligand6
FDA-approved for postherpetic neuralgia1
Evidence for efficacy in DPN7
Generally well tolerated1
• Topiramate
− Small study suggested efficacy8
1. Physician’s Desk Reference. Montvale, NJ: Thomson PDR; 2004. 2. Eisenberg E,
et al. Neurology 2001;57:505-9. 3. Simpson DM, et al. Neurology. 2000;54:21152119. 4. Simpson DM, et al. Neurology. 2003; 60:1508-1514. 5. Zakrzewska JM, et al.
Pain. 1997;73:223-230. 6.Gee NS, et al. J Biol Chem. 1996;271:5768-5776. 7.
Backonja M, et al. JAMA. 1998;280:1831-1836. 8. Edwards KR, et al. Neurology
2000; 54: A81(abstract).
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Clinical Management - Antidepressants
• Tricyclic Antidepressants
− Block reuptake of NE, serotonin at presynaptic
neurons
− Block postsynaptic receptors
− Thought to enhance the descending inhibitory
pathway, and decrease pain signaling
− Analgesic effects are independent of
antidepressant effects
− Low dose
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10
TCAs: Efficacy
• Meta-analysis of 13 studies of TCAs across pain
conditions
• Number needed to treat (NNT) for 50% pain relief: 2.9
•
•
(95% CI, 2.4-3.7)
− Imipramine (4 reports): NNT=3.7 (2.3-9.5)
− Desipramine (2 reports): NNT=3.2 (1.9-9.7)
Analysis of DPN trials only: NNT=3.4 (2.6-4.7)
Analysis of PHN trials only: NNT=2.1 (1.7-3.0)
McQuay HJ, et al. Pain 1996;68:217-227.
Collins SL, et al. J Pain Symptom Manage. 2000;20:449-458.
31
TCAs: Mechanism of Action
• Block reuptake of noradrenaline and serotonin by
•
•
presynaptic neurons1
− Raises synaptic neurotransmitter concentrations
Analgesic effects independent of antidepressive
effects2
− Analgesia usually occurs at a lower dose
Inhibition of noradrenaline and serotonin reuptake is
thought to enhance the descending inhibitory
pathway3,4
1. Reisner L. Curr Pain Headache Rep. 2003;7:24-33.
2. Vaillancourt PD, Langevin HM. Med Clin North Am. 1999;83:627-643.
3. Ashburn MA, Rice LJ, eds. The Management of Pain. New York: Churchill Livingstone; 1998
4. Belgrade MJ. Postgrad Med. 1999;106:127-140.
32
TCAs: Safety and Tolerability
• Up to 5% of patients experience significant adverse
effects of TCAs
• Anticholinergic effects
•
•
•
•
•
−
−
−
−
−
−
Blurred vision
Dry mouth
Sinus tachycardia
Constipation
Urinary retention
Confusion/memory impairment
Sedation, potentiation of CNS depressants
Orthostatic hypotension, dizziness
Hypotension
Weight gain
Reflex tachycardia
Hardman JG, Limbird LE, eds. Goodman & Gilman’s The Pharmacological Basis of
Therapeutics. 10th ed. New York: McGraw Hill; 2001.
Andreasen NC, Black DW. Introductory Textbook of Psychiatry. 3rd ed. Washington,
DC: American Psychiatric Press; 2001.
33
11
TCAs: Dosing Recommendations
• Beginning dosage: 10-25 mg every night
• Titration: increase by 10-25 mg/d every 3-7 days as
tolerated
• Maximum dosage: 75-150 mg/d
• Duration of adequate trial: 6-8 wk with at least 1-2 wk
at maximum tolerated dosage
Dworkin RH, et al. Arch Neurol. 2003;60:1524-1534.
34
Clinical Management - Antidepressants
• SNRIs
− Venlafaxine (Effexor XR)
− Duloxetine* (Cymbalta)
− Specifically inhibit norepinephrine reuptake
•SSRIs
–Sertraline (Zoloft)
–Fluoxetine (Prozac)
–Paroxetine (Paxil)
–Specifically inhibit serotonin reuptake
35
Poll
• Do you feel that clinicians are more likely to
accept your recommendation for a topical
product than for an oral medication?
36
12
Clinical Management - Topicals
• Capsaicin
− OTC, PHN/DPN labeling
− Depletes substance P from the peripheral nerve
endings
− Takes time for optimal response
• Lidocaine Patch
− Blocks the movement of Na across neuronal cell
membranes
− Prevents the APs from being transmitted
− Can be worn up to 12 hours a day
37
Local and Regional Treatment Measures
• Lidocaine patch
− Indicated for PHN1
− Favorable side effect profile1
• Erythema, edema, abnormal sensation at application site
− Suggested efficacy in pilot studies in DPN2 have not been
−
confirmed in controlled trials
Limitations
• Topical route of administration
• Application of the patch is painful
• Capsaicin
− One study found effective pain relief compared with amitriptyline3
− Other studies have given mixed results4,5
1. Lidoderm [prescribing information]. Chadds Ford, Penna: Endo Pharmaceuticals;
2004. 2.Dworkin R, et al. Presented at: American Pain Society 22nd Annual Meeting.
March 20, 2003. 3. Biesbroeck R, et al. Adv Ther 1995;12:111-20. 4. Low PA, et al. Pain
1995;62:163−168. 5. Capsaicin Study Group. Arch Intern Med 1991;151:2225−2229.
38
Pharmacological Options: Other Agents
•
•
•
•
•
Opioids
NSAIDs
Tramadol
Baclofen
− Anecdotal reports suggest some benefit
Antiarrhythmics
− Mexiletine effective in some but not all
trials1,2
1. Oskarsson P, et al. Diabetes Care 1997;20:1594-1597.
2. Jarvis B, Coukell AJ. Drugs 1998;56:691-707.
39
13
Opioids: Mechanism of Action
• Bind to opioid receptors
− G-protein linked cell signaling molecules
− Endogenous ligands are the enkephalins, endorphins, and
dynorphins
− Physiological role not completely understood
• Opioid analgesia produced at the spinal and
supraspinal levels
• Enhance activity of the descending pain modulation
pathway
Hardman JG, Limbird LE, eds. Goodman & Gilman’s The Pharmacological
Basis of Therapeutics. 10th ed. New York: McGraw Hill; 2001.
40
Opioids: Efficacy
• Efficacy in neuropathic pain remains controversial1-4
• Some opioids have shown benefit in PHN5-8
• Doses needed for neuropathic pain may be higher
than those needed to treat nociceptive pain3,9,10
1. Wall PD, Melzack R, eds. Textbook of Pain. 4th ed. Edinburgh: Churchill Livingstone;
1999. 2. Vaillancourt PD, Langevin HM. Med Clin North Am. 1999;83:627-643. 3.
Benedetti F, et al. Pain. 1998;74:205-211. 4. Galer BS. Neurology. 1995;45(Suppl 9):
S17-S25. 5. Raja SN, et al. Neurology. 2002;59:1015-1021. 6. Rowbotham MC, et al.
Neurology 1991;41:1024-1028. 7. Max MB, et al. Clin Pharmacol Ther. 1988;68:217227. 8. Watson C, Babul N. Neurology. 1998;50:1837-1841. 9. Cherny NI, et al.
Neurology. 1994;44:857-861. 10. Jadad AR, et al. Lancet. 1992;339:1367-1371.
41
Opioids: Dosing Recommendations
• Extended-release opioids should be given by the
clock, not on an as-needed basis
• Initiate at a low dosage
• Titrate based on response
• Maximum dosage based on adequate pain relief and
tolerability
Kalso E, et al. Eur J Pain. 2003;7:381-386.
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14
Mechanisms of Action – AEDs
Multiple and overlapping Mechanisms
• Block Na channels
− Decreases frequency of the AP
• Block Ca channels
− Decrease excitation, release of excitatory NTs
• Attenuation of Ca influx into Presyn. Terminal
− Reduction of Ca influx decreases the release of excitatory
NTs
− Decrease # of APs
43
Mechanisms of Action – AEDs
Multiple and overlapping Mechanisms
• Decrease Glutamatergic Transmission
− Inhibit glutamate receptor
− Decrease glutamate synthesis/release
• Increase GABA-ergic Transmission
− Increase GABA receptor activity
− Increase GABA synthesis/release
− Decrease GABA reuptake
44
Pregabalin and Gabapentin
• Binds to the alpha2-delta subunit of voltagegated calcium channels (N-type and P/Q-type)
− Modulates the calcium channel and reduces
calcium influx
− Reduces the release of NTs from hyperexcited
presynaptic neurons
45
15
46
Pregabalin and GabapentinRationale for Newer Therapy
• Are NOT:
− Calcium channel blockers!!
− Calcium channel blockers (amlodipine) bind to the alph1
subunit of L-type calcium channels
• Directly blocks the channel pore
• Effect the peripheral vascular smooth muscle
• DO NOT:
− Bind to GABA
− Augment GABA responses
− Act like GABA uptake inhibitors
47
Different Chemical Structures
CO2H
NH2
Pregabalin
H2N
CO2H
GABA
NH2
CO2H
Gabapentin
Lyrica® (pregabalin) capsules CV [package insert]. New York, NY: Pfizer Inc; 2005;
Neurontin® (gabapentin) [package insert]. New York, NY: Pfizer Inc; 2004.
48
16
Gabapentin and Pregabalin Binds to the α 2 - δ
Subunit of Voltage-Gated Ca2+ Channels in the
Central Nervous System
Presynaptic
Α2- δ
subunit
Ca2+
channel
Neurotransmitters
Postsynaptic
Schematic representation of pregabalin’s proposed mechanism of action
• Pregabalin selectively binds to α2 - δ subunit of calcium channels
•
•
•
•
Modulates calcium influx in hyperexcited neurons
Reduces neurotransmitter release
Pharmacologic effect requires binding at this site
The clinical significance of these observations in humans is currently unknown
49
Taylor. CNS Drug Rev. 2004;10:183-188.
Pharmacokinetic Profile
The Logic for a New Drug
Variable
Gabapentin
Absorption
Bioavailability
Dosage increases
Exposure
Plasma half-life
Steady state
Protein binding
Metabolized
Renal excretion
Pregablin
Slow
Rapid
Food affects absorption
Various
No food effect
Dose proportional
Non-Linear
Linear and Predictable
Dose related
Predictable levels
BID or TID dosing
BID or TID dosing
Slow dose adjustment
Fast dose adjustment
Varied
Predictable levels
Yes
Predictable levels
Removed by dialysis
Adjust in renal
impairment
Removed by dialysis
Adjust in renal
impairment
Lyrica® (pregabalin) capsules CV [package insert]. New York, NY: Pfizer Inc; 2005
Neurontin® (gabapentin) [package insert]. New York, NY: Pfizer Inc; 2004;.
50
Poll – True or False?
• A medication that has dose dependent
absorption rates is safer for a patient than
one that has linear absorption.
51
17
Dose Response
Pregabalin Versus Gabapentin
High Bioavailability
Linear PK Profile
18
Steady State Cmax (µg/mL)
16
Pregabalin
14
Gabapentin
900 mg 60%
12
10
All doses
8
≥ 9 0%
2400 mg 34%
3600 mg 33%
6
4
1800 mg
Recommended
dose
Pregabalin
Gabapentin
2
0
1200 mg 47%
0
600 1200 1800 2400 3000 3600 4200 4800
Dose (mg/d)
Lyrica® (pregabalin) capsules CV [package insert]. New York, NY: Pfizer Inc; 2005; Neurontin®
(gabapentin) [package insert]. New York, NY: Pfizer Inc; 2004; Wesche, Bockbrader. Presented
at: 24th Annual Scientific Meeting of the American Pain Society; 2005.
52
Open-Ended Question
Please use the chat window to respond.
• What do you recommend a patient do if they
are not sure a medication is working?
53
Refractory Pain Study —Design Overview
Treatment
period 1
Drug holiday
1
Treatment
period 2
Drug holiday
2
Treatment
period 3
Drug holiday
3
Treatment
period 4
Drug holiday
4
Treatment
period 5
3 months
3-28 days
3 months
3-28 days
3 months
3-28 days
3 months
3-28 days
3 months
Relapse
Relapse
Relapse
Relapse
“How much has your pain worsened since discontinuing study medication?”
Not at all = 1
A little worse =2
√
Moderately worse =3
√
Much worse =4
√
Very much worse =5
Relapse
Treatment period = 3-month open-label treatment period with pregabalin 150-600 mg/day
ADA, June 2005
54
18
Pregabalin treatment
Relapse visit (drug holiday)
Moderate
Baseline
100
90
80
70
60
50
40
30
20
10
0
Severe
Mild
Mean SF-MPQ VAS/Relapse VAS scores
Pain Reported on Pregabalin Treatment*
and During Drug Holidays
3
months
DH 1
6
months
DH 2
9
months
DH 3
12
months
DH 4
15
months
DH = drug holiday
*15-month open-label pregabalin treatment analysis
55
ADA, June 2005
% of patients
Distribution of Pain Severity at Baseline
and 15 Months
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
1
36
41
None/mild
Moderate
Severe
36
63
23
Baseline
15 months
No/Mild Pain: 0 – 39; Moderate Pain: 40 – 69; Severe Pain: ≥70 on SF-MPQ pain VAS
15-month analysis (LOCF).
56
ADA, June 2005
Dizziness / Somnolence
• Mild, moderate
• Occurred soon after initiation of therapy
• Majority resolved before end of the study
• Most common reason for discontinuation
− Dizziness
3%
− Somnolence 2%
57
19
In Conclusion
• DPN is a painful, debilitating complication of
diabetes
• Patients have difficulty finding relief
• Current medications are somewhat effective
and duration of effectiveness is varied
• Newer medications have been focused on
improving outcomes without side effects
• Patients need to be counseled on medication
expectations, dosing and side effects
• Pharmacists are in a unique position to
counsel patients.
58
20