Download Chronic Nonmalignant Pain Treatment

Multimodal, Mechanism-Based
Approaches to Chronic Non-Malignant
Pain Pharmacotherapy
Daniel Wermeling, Pharm.D.
Professor
University of Kentucky
College of Pharmacy
Chronic Pain Types
Nociceptive vs Neuropathic Pain
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Chronic non-malignant pain can have either or both
Neuropathic is more common problem
Neuropathic pain originates from stimulation and
damage to afferent nociceptive nerve fibers, not the
receptors
Syndrome results from continuous abnormal
processing of sensory input and subsequent
physiologic (plasticity) changes within the nervous
system
Modulation and transmission functions become
dysfunctional
Peripheral and Central
Sensitization: Mechanisms of
Chronic Neuropathic Pain
Post-Injury Afferent Nerve Changes
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Some nerves degenerate and the lesions trigger
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Expression of Na+ channels on damaged C-fibers
Expression of Na+, α-adrenoceptor on uninjured fibers
Promotes hyperexcitation and spontaneous nerve firing
Sensitization
Acute to Chronic Continuum
Baclofen
Opioids
Clonidine
GABAB
μ
δ
C-Fiber
Central Axon
α2
5-HT3
Glutamate
Guanyl
Synthase
Substance P
Closed K+
Channel
K+
NMDA
Ca2+
AMPA
K+
GABAA
5-HT1B
Dorsal Horn Cell
Basbaum A. PNAS. 1999;96:7739-7743.
NK-I
Na+
NO
Ca2+
c-fos
expression
NO Synthase
Mg2+ Plug
Removed
Neuropathic Pain Sensations
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Allodynia - Painful response to a non-noxious
stimulus (rubbed by a feather)
Hyperalgesia – exaggerated painful perception to
normally noxious stimulus (like a pin-prick)
Burning (like foot on a hot plate)
Tingling
Electrical shock, shooting
Closest example of “hitting your funny bone”
Disability is high because of pain symptoms
Painful Peripheral Neuropathies
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Focal/multifocal
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Entrapment
Phantom limb/stump
Post-trauma
Post-herpetic
Diabetic
Ischemic
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Generalized (poly)
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Diabetes
Alcohol/toxins/drugs
HIV
Amyloidosis
Vit B deficiency
Hypothyroidism
Other Painful Lesions
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Lesions of CNS
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Spinal cord injury
Brain infarction (thalamus and brainstem)
Spinal infarction
Multiple sclerosis
Complex Regional Pain Syndromes or reflex
sympathetic dystrophy (RSD)
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Type 1 – noxious event to tissues, like trauma
Type 2 – peripheral nerve/root injury, brachial plexus
Sympathetic nervous system also damaged
Impact of Chronic Pain on the
Dimensions of Quality of Life
Physical
• Functional ability
• Strength/fatigue
• Sleep and rest
• Nausea
• Appetite
• Constipation
Pain
Social
• Caregiver burden
• Roles and relationships
• Affection/sexual function
• Appearance
Adapted from Ferrell et al. Oncol Nurs Forum. 1991;18:1303–9.
Psychological
• Anxiety
• Depression
• Enjoyment/leisure
• Pain distress
• Happiness
• Fear
• Cognition/attention
Spiritual
• Suffering
• Meaning of pain
• Religiosity
The Terrible Triad of Chronic Pain
Suffering
Chronic
Pain
Sleeplessness
Sadness
National Institute of Neurological Disorders and Stroke, 1989.
Neuropathic Pain:
First-Line Pharmacotherapy
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Supported by good evidence
– Alpha-2-delta nerve modulators: Gabapentin*
and Pregabalin*
– Antidepressants: TCAs* and duloxetine*
– Carbamazepine for TN*
– Lidocaine patch 5%*
– Opioid analgesics, including tramadol
*FDA-approved for the treatment of postherpetic neuralgia. †Not FDA-approved for analgesia. Carbamazepine: FDA-approved for
trigeminal neuralgia. ‡FDA-approved for the treatment of painful diabetic neuropathy.
1. Dworkin RH et al. Arch Neurol. 2003;60:1524-1534. 2. FDA news, 2004. Available at: http://www.fda.gov/bbs/topics/news/
2004/NEW01113.html. Accessed March 29, 2006. 3. Lesser H et al. Neurology. 2004;63:2104-2110.
Neuropathic Pain
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Other commercially-available treatments
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Other AEDs
 Topiramate, oxcarbazepine, levetiracetam,
zonisamide, tiagabine
Other ADs
 SNRI (venlafaxine), SSRI (paroxetine,
citalopram), others (maprotiline, bupropion)
Neuropathic Pain
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Other commercially-available treatments
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Alpha-2 adrenergic agonists
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NMDA antagonists
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Ketamine, memantine
Other sodium channel blockers
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Tizanidine, clonidine
Mexiletine, tocainide, flecainide
Cannabinoids
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THC, nabilone
Linkage of Symptom to Treatment
Symptom Pathol.
Process
Targets
Mech. Of Options
Action
Spontane Ectopic
ous
nerve
Shooting impulse
Pain
Sodium
Channel
Selective TCAs
Sodium
Topical
Channel Lidocaine
Blocker
SNRIs for Treatment of
Neuropathy
Treatment of Depression and Pain
Tramadol/Tapentadol
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Central analgesic
MOA – weak mu receptor agonist and weak
NE and SE reuptake inhibition
Synergy between mechanisms
Useful in neuropathic pain
Start low and increase dose to tolerance
Dizziness, vertigo, GI, headache
Avoid use in seizure risk patient
Abuse liability and recently a controlled
substance in KY
Antianxiety Agents
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In chronic pain, benzodiazepines can relieve pain by
reducing anxiety associated with the chronic pain
state and resulting insomnia and muscle tension
Also used as anticonvulsants and antispasmodics for
neuropathic pain
Adverse effects: cognitive impairment, physical
dependence, worsen depression, additive CNS
depressant effects when combined with opioid
Skeletal Muscle Relaxants
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Agents include baclofen, carisoprodol,
chlorzoxazone, cyclobenzaprine, diazepam,
metaxalone, methocarbamol, orphenadrine,
tizanidine
Beneficial for pain states involving muscle spasm
Interrupt pain-spasm-pain cycle
Improve range of motion, help patients regain
function, facilitates rehab and therapeutic exercise
Adverse effects: Drowsiness, dizziness, lightheadedness, fatigue, sedation
Corticosteroids
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Powerful anti-inflammatory agents that
reduce nociception
Often used for tumor-related pain
Variety of adverse effects from systemic
administration; should be limited to 1 to 2
weeks of therapy
Injections widely used for tendonitis, bursitis,
tenosynovitis, epicondylitis
Botulinum Toxins
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Neurotoxins block acetylcholine release at
neuromuscular synapses, causing paralysis
May also have independent analgesic effects
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Demonstrated efficacy
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Anti-inflammatory, blocking release of glutamate, reducing
concentrations of substance P
In myoclonus, tension-type headache, trigger points,
myofascial pain, back pain, cervical dystonia and other focal
dystonias, and spastic disease states
Usually reserved for refractory cases
Data Collection and Assessment
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Standard assessment protocol required
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Have patient describe their pain through structured
interview. How does it affect daily living?
Physical examination and history
Supportive tests, labs , radiology, nerve conduction
Psychological and Social assessment
Rule out treatable causes of pain, establish diagnosis
Begin pharmacotherapy protocols based on symptoms
Substance abuse history
Medication History
Goal is to improve daily function and quality of life
General Approach to Pharmacologic
Treatment
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Nociceptive pain, acute pain, is easy to treat with
conventional pharmacologic agents
Chronic pain is not acute pain that persists
Treating chronic pain with acute pain models will
have poor outcomes
Neuropathic pain is not easily treated with
conventional analgesics and requires a multimodal
approach
There can be a nociceptive component
Most effective agents affect nerve transmission
General Neuropathic Pain
Pharmacotherapy
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Tricyclic antidepressants, such as amitriptyline, or
anti-epileptic drugs, such as gabapentin or
pregabalin are drugs of choice
Topical products such as lidocaine and capsaicin for
certain focal neuropathy
Opioids can be adjuncts but must be used at much
higher doses than nociceptive pain – big risks for
little benefit in general
Some patients receive nerve blocks, spinal cord
stimulators (Jerry Lewis), &/or IT delivery
General Considerations
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Oral conservative therapy is first line
Titrate upward for trials with each medication
Additional medications to be added
General outlines “work” for back, diabetic, and other
neuralgias
Herpetic neuralgia responds to topical capsaisin and
lidocaine patch
Multimodal therapy may advance to IT delivery with
opiates, clonidine, ziconotide
Simplistic Algorithm for Peripheral
Neuropathic Pain
Finnerup, Pain 2005
Or Capsaicin
Cream
Reassessment is Critical
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Was the medication successful in reducing
any pain or to some meaningful degree?
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What is meaningful? Expectations?
? 50% reduction in pain score ?
Do they feel better or worse?
Can they do more than they used to?
Document the improvement
Discontinue if no benefit!!
Too many patients on cocktails
Add another medication for a trial and repeat
Opioids for CNMP
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Consensus statement, American Academy of Pain
Must alleviate under-treated pain and suffering
Places much greater emphasis on thorough patient
assessments and frequent evaluations, creating
treatment plans and documenting effects
Individualized treatment plans
Written agreements (contracts) with patients
Functional improvement outcomes must be overall
goal
Dependence-Producing
Agents in Chronic Pain:
Basic Principles
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First line use for breakthrough CNP episodes
Replace with non-narcotic as soon as possible
Chronic therapy
– Use SR opioids, or
– Methadone, since it has dual action at NMDA receptor
In general use these agents with caution:
– Potential for abuse is great
– Patients use as a shortcut to controlled physical
activities
– Detoxification may be necessary at some point to
achieve optimal analgesia. Well-defined, short-term
therapy is essential
Long-term Opioid Use Linked to Worse
Outcome After Back Injury
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Opioid Dependence Risk is Great and Results in
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Longer disability (29 vs 17months)
2.5 x more likely to have surgery
2.5 x more likely to have antisocial disorder
2 x more likely to have had pre-injury substance use
disorder
2 x more likely to have depressive or anxiety disorder
90% still have moderate to severe pain
Mayer 2007, Erickson Pain 2007
Low Back Pain: Nociceptive vs
Neuropathic Pain
Neuropathic
Nociceptive
• Caused by activity
in neural pathways
in response to
stimuli potentially
damaging to tissue
• Responsive to
analgesics
Mixed
• Caused by both
primary injury and
secondary effects
• May require polypharmacotherapy
• Initiated or caused
by primary lesion
or dysfunction in
the nervous system
• Responsive to
neuromodulators
• May require polypharmacotherapy
1. International Association for the Study of Pain. IASP pain terminology. Available at: http://www.iasp-pain.org/terms-p.html#
Neuropathic%20pain. Accessed March 9, 2006. 2. Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice.
Philadephia, Pa: FA Davis Co; 1996:248-276. 3. NPC/JCAHO. Pain: Current Understanding of Assessment, Management, and
Treatments. December 2001.
Pharmacological Treatment Options
for Low Back Pain
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Nonspecific analgesics
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NSAIDs
Opioids
“Muscle relaxants”
Analgesic antidepressants
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Alpha-2 adrenergic
agonists
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TCAs
SNRIs
Others
Tizanidine
Topical LA
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For neuropathic pain
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All nonspecific drugs
AEDs
Others
Interventional Treatment Options
for Low Back Pain
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Injection therapies
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Neural blockade
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Epidural steroid injections
Facet steroid injections
Botulinum toxin injection
Radiofrequency median branch block
Implant therapies
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Spinal Cord Stimlators
Neuraxial infusion
Nonpharmacologic Treatment
Options for Low Back Pain
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Physical medicine approaches
Psychological approaches
Lifestyle changes
Conclusion
CNMP is a difficult, common medical
problem
 Treatment is complex and multimodal
 Pharmacotherapy approaches are
complex and use medications alone
and in combination
 Off-label drug prescribing is common
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Conclusions
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Screen and assess patients for pain
complaints
Monitor and document findings to protect the
patient, society and medical and pharmacy
clinicians
Modify to decrease pain symptom and
associated morbidity
Omnibus goal – Promote optimal
functional living
Pharmacists Have an Obligation to
Relieve Pain
“I will consider the welfare of humanity
and relief of human suffering my
primary concerns.”
Oath of a Pharmacist