Transcript Pharmacological Management for Failed Back Surgery Syndrome

Pharmacological Management for
Failed Back Surgery Syndrome
Richard K. Osenbach, M.D.
Director, Neuroscience Program
Director, Neurosurgical Services
Cape Fear Valley Health System
Fayetteville, NC
Failed Back Syndrome
Surgery probably not indicated in the first
place
 Clear indications for surgery, but the surgery
did not correct the problem
 Significant complication of surgery with
production of pain generator
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Drug for Treatment of FBSS
NSAIDS and Coxibs
 Corticosteroids
 Anti-epileptics
 Anti-depressants
 Opioids
 Topical agents
 Miscellaneous drugs
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Antidepressant Analgesics
“The results suggest to us that
antidepressants may have an analgesic
action which is independent of their
mood-altering effects”
Merskey & Hester 1972
Antidepressant Analgesics
Merskey & Hester, 1999
Anti-depressants indicated in patients with a
major concomitant depressive component but
there is a separate analgesic action (1960s)
 TCA first choice of drug therapy for chronic pain
 Little evidence to support one drug over another
 More studies needed comparing antidepressant
siwht other drugs such as anti-convulsants
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Descending Pain Modulation
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Endorphin link from PAG to
pontine raphe nuclei
Serotonergic conection to
spinal dorsal horn
Noradrenergic pathway from
locus ceruleus to dorsal horn
Antidepressant Analgesics
Pharmacology
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Well-absorbed following oral administration
First-pass hepatic metabolism
Highly bound to serum proteins
Highly lipophilic – large volume of distribution
Long elimination half-life (1-4 days)
Active metabolites (eg. imipramine to desipramine)
Oxidized by hepatic microsomal system
Serum levels available but correlation with analgesia is
unclear
Antidepressant Analgesics
Current Evidence
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Analgesic action of some antidepressants relieves all
components of neuropathic pain
RCT have shown clear separation of analgesic and
antidepressant effects
Although other agents (eg anti-epileptics)) may be regarded as
1st line therapy over antidepressants, there is no good
evidence for this practice
More selective agents are either less effective or not useful
(serotonergic, noradrenergic)
Because of incomplete efficacy, combination therpay may be
needed
Comparative data regarding other drugs using NNT figures
now exists
Antidepressant Medications
Tricyclic-type AD
Amitriptyline
Nortriptyline
Clomipramine
Desipramine
Impramine
Doxepin
Maprotiline
Ritanserin
Trazadone
Trimipramine
SSRI-type AD
Fluoxetine
Paroxetine
Ritanserin
Citalopram
Fluvoxemine
Sertraline
SNRI antidepressant
Venlaflexine
Antidepressants
Mechanism of Action
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Alteration of monamine
neurotransmitter levels at
synapse
Pre-synaptic blockade of
serotonin and NE reuptake
by amine pump (immediate
effect)
Anticholinergic muscarinic
effects
Antihistaminergic effects
(H1 and H2)
Antidepressants for LBP-RCT
Author
Agent
No.
Effect
Comments
Jenkins et al., 1976
Imipramine 50mg
4 weeks
44/59
No
Parallel design
Alcott et al., 1982
Imipramine 150mg
8 weeks
41/50
No
Parellel design; poss
role for pain
Godkin et al., 1990
Trazadone 200mg
42
No
Parellel design
Serotonergic agent
Usha et al., 1996
Fluoxetine 20mg
Elavil 25mg
Placebo
4 weeks
59
Yes
Parallel design
Fluoxetine more
effective with fewer
SE
Atkinson et al., 1998
Nortriptyline 100mg
Inert placebo
57/78
Yes
Parallel design
Non-depressed pts
Dickens et al., 2000
Paroxetine 20mg
61/92
No
Parellel design
Antidepressants in Neuropathic Pain-RCT
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Watson et al.: reviewed 29 randomized clinical trials
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Mixed SN agents – 18/21 (86%) Positive effects
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Amitriptyline 10/13, Imipramine 5/5,Doxepin 1/1, Venlafexline
2/2
Noradrenergic agents – 10/12 (83%) Positive effects
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16 involved PHN or PDN
Nortriptyline 3/4, desipramine 4/5, maprotiline 2/2, bupropion
1/1
Serotonergic agents – 4/5 (80%) Positive effects
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Paroxetine 1/2, clomipramine 2/2, citalopram 1/1
Guidelines for Use of Antidepressants
in Pain Management
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Eliminate all other ineffective analgesics
Start low and titrate slowly to effect or toxicity
Nortriptyline or amitriptyline for initial treatment
Move to agents with more noradrenergic effects
Consider trazodone in patients with poor sleep pattern
Try more selective agents if mixed agents ineffective
Do NOT prescribe monoamine oxidase inhibitors
Tolerance to anti-muscarinic side effects usually takes
weeks to develop
Withdraw therapy gradually to avoid withdrawal syndrome
Adverse Effect of Antidepressants
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Anti-cholinergic autonomic effects (TCAs)
Allergic and hypresensitivity reactions
Cardiovascular effects
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CNS effects
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Orthostatic hypotension (avoid imipramine in elderly)
Quinidine-like cardiac effects
Sedation, tremor, seizures, atropine-like delerium, exacerbation
of schizophrenia/mania
Acute overdose may be fatal (>2000mg)
Withdrawal reactions
Adverse Effects of 2nd Generation AEDS
Anticonvulsant Agents (AEDS)
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Similarities in the pathophysiology of neuropathic pain and epilepsy
 Changes in sodium and calcium channels
 Spontaneous firing at ectopic sites in the sensory system
All AEDS ultimately (directly or indirectly) act on ion channels
Efficacy of AEDS has been most clearly established for neuropathic
conditions characterized by episodic lancinating pain
Most clinical studies have focused on diabetic neuropathy and
postherpetic neuralgia
Use of AEDS in patients with FBSS is nearly entirely empiric
AEDS Studied in Neuropathic Pain
Mechanisms of Selected AEDS
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Carbamazepine (Tegretol)
 Modulates voltage-gated Na+ channels
 Reduces spontaneous activity in experimental neuromas
 Inhibits NE uptake; promotes endogenous descending inhibitory mechanisms
Oxcarbazepine (Trileptal)
 Modulates Na+ and Ca+2 channels, incease K+ conductance
 Lacks toxicity of epoxide metabolites
Lamotrigine
 Blocks voltage-gated Na+ channels
 Inhibits glutamate release from pre-synaptic neurons
Gabapentin (Neurontin)
 Structural analog of GABA
 Binds to voltage-dependent calcium channels
 Inhibits EAA release; Interacts with NMDA receptor at glycine site
Pregabalin (Lyrica)
 Binds to voltage-gated calcium channels
Adverse Effects of AEDS
Drowsiness and cognitive dysfunction
 Weight changes
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Weight gain – gabapentin
 Weight loss – topiramate, zonisamide
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Visual side effects
Angle closure glaucoma – topiramate
 Hallucinations - zonisamide
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Gabapentin in PHN
Pregabalin for Diabetic Neuropathy
Gabapentin in Diabetic Neuropathy
Pregabalin for PHN
WHO Classification of Opioids
Weak Opioids
 Codeine
 Dihydrocodeine
 Dextropropoxyphene
 Tramadol
Strong Opioids
 Morphine
 Methadone
 Fentanyl
 Meperidine
 Oxycodone
 Buprenorphine
 Levorphanol
 Dextromoramide
Gabapentin vs. Pregabalin
Functional Classification of Opioids
Full Agonists
 Morphine
 Fentanyl
 Hydromorphone
 Codeine
 Methadone
 Tramadol
 Meperidine
Partial Agonists
 Buprenorphine
 Pentazocine
Agonist-Antagonists
 Nalbuphine
 Nalorphine
Antagonists
 Naloxone
 Naltrexone
Bioavailability of Common Opioids
Opioid
Hydromorphone
Morphine
Meperidine
Codeine
Oxycodone
Levorphanol
Tramadol
Methadone
Approximate Bioavailability (%)
20
30
30
60
60
70
80
80
Adverse Effects of Opioids
Common
Nausea/vomiting
Constipation
Urinary retention
Sedation
Cognitive impairment
Pruritis
Occasional
Hallucinations
Myoclonus
Mood changes
Anxiety
Rigidity
Dry mouth
Gastric stasis
Bronchoconstriction
Rare
Respiratory dep.
Seizures
Delerium
Hyperalgesia
Allodynia
Tolerance, Physical Dependence, Addiction
Opioids for Chronic Non-Malignant Pain
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Well-established and accepted for acute pain and cancer
pain
Extrapolation of outcomes in cancer pain to non-malignant
pain may be flawed
Information is more anecdotal, contradictory, philosophical,
and/or emotional than scientific
Limited number of well-designed RCT with inconclusive
results
Reduction in pain scores of around 20% without major
benefits on function or psychological outcomes
Principles of Opioid Therapy in
Chronic Non-Malignant Pain
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Opioid use will provide analgesic benefit for a selected
subpopulation of patients
Less evidence exists in regard to improvement in
function
Benefits outweigh risks in well-selected patients
Most benefit in patients with pain from established
nociceptive/neuropathic conditions
Identification of other appropriate patients is problematic,
and valid diagnostic criteria do not exist
Principles of Opioid Therapy in Chronic
Non-Malignant Pain
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Identification of realistic goals of treatment
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Opioids should only be viewed as part of a
multimodality approach to pain management
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Evaluate as a whole
Not necessarily achievable as single parameters
Provide subjective pain reduction so that the patient can
better cope with other treatment modalities
Best practice – prescribe a trial of opioids and
withdraw use if the provision of analgesia does not
result in functional improvement
Implementation of Opioid Therapy
Prerequisites
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Failure of pain management alternatives
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Not a last resort
Physical and psychosocial assessment by
multidisciplinary team or at least two practitioners
 Consider history of substance abuse as a relative
contraindication
 Decision to prescribe by multidisciplinary team or
at least two practitioners
 Informed written consent
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Implementation of Opioid Therapy
Therapeutic Trial Period
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Appropriate oral or transdermal drug selection
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Long-acting µ-receptor agonist (Methadone)
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Effects on non-opioid receptors (NMDA, serotonin, NE)
Slow-release preparation of shorter-acting agents
Defined trial period with regular assessment and review
Opioid dose adjustment or rotation as needed
Decision for long-term treatment predicated upon
demonstration of pain relief and/or functional
improvement
Implementation of Opioid Therapy
Long-Term Therapy
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Opioid contract
Single defined prescriber
Regular assessment and review
Routine urine and serum drug screen
Ongoing effort to improve physical, psychological,
and social function as a result of pain relief
Continued multidisciplinary approach to pain
Defined responses to psychosocial or behavioral
problems (addiction, diversion, etc)
Opioid Therapy - RCT
Pain Type
Nociceptive
Study
Results
Arner & Meyerson, 1988
Placebo
Pos
Kjaersgaard-Anderson, 1990
Paracetamol
Pos***
Placebo
Neg
Dellemijn & Vanneste, 1997
Placebo/Valium
Pos
Kupers, et al., 1991
Placebo
Pos
Rowbotham et al., 1991
Placebo
Pos
Arner & Meyerson, 1988
Placebo
Neg
Kupers, et al., 1991
Placebo
Neg
Moulin et al., 1996
Benztropine
Pos***
Placebo
Pos***
Placebo/Bupiv
Pos
Neuropathic Arner & Meyerson, 1988
Idiopathic
Control
Unspecified Arkinstall et al., 1995
Mays et al., 1987
Opioid Therapy – Prospective
Uncontrolled Studies
Pain Type
Reference
Results
Nociceptive
Neuropathic
McQuay et al., 1992
Fenollosa et al., 1992
McQuay et al., 1992
Urban et al., 1986
Pos
Pos
Mixed
Pos
Idiopathic
McQuay et al., 1992
Mixed/Unspecified Auld et al. 1985
Gilmann & Lichtigfeld, 1981
Neg
Pos
Pos
Penn and Paice, 1987
Pos
Plummer et al., 1991
Mixed
Tramadol for LBP
Conclusions
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Long-term opiate therapy may benefit patients with
chronic pain syndromes of nociceptive and/or
neuropathic origin
Nociceptive pain tends to respond more favorably
than neuropathic pain
Patients with ill-defined or “idiopathic” pain
syndromes respond less well to long-term opiates
Positive effects are larger and more common in
uncontrolled trials than in prospective RCTs
Establishing a correct diagnosis and underlying cause
of pain is essential when considering long-term
opioid therapy
Equianalgesic Doses of Opiods
Drug
Morphine
Equianalgesic Dose
10mg
Meperidine
100
Codeine
90
Dihydrocodeine
60
Tramadol
50
Nalbuphine
10
Oxycodone
7.5
Leveorphanol
2
Hydromorphone
2
Butorphanol
2
Oxymorphone
Methadone
Buprenorphine
1.5
1
0.3
Cannabinoids
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Strong laboratory data supporting an analgesic effect of cannabinoids
Efficacy of cannabinoids in human has been modest at best
Effectiveness hampered by unfavorable therapeutic index
Campbell (2001) – systematic review of 9 clinical trials of
cannabinoids
 Cancer pain (5), Chronic non-cancer pain (2), acute pain (2)
 Analgesic effect estimated equivalent to 50-120mg codeine
 Adverse effects reported in all studies
RCT have shown modest benefits when compared with placebo
Increased incidence of psychiatric illness and cognitive dysfunction
Topical Treatments
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Aspirin preparations
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Local anesthetics
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Topical 5% lidocaine patch
EMLA
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Eg. aspirin in choroform
Eutectic mixture of local anesthetics
Capsaicin
Botulinum Toxin for Chronic LBP
Botulinum Toxin for Chronic LBP
World Congress
Selection of Neuropathic Analgesics
General Considerations
Safety
 Tolerability
 Patient convenience – ease of use
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Once daily vs. multiple dosing
 Small pills vs. big pills
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Effectiveness
Topical Agents
Lidocaine
Lidocaine Patch for LBP
Lidocaine Patch for LBP
Alpha2 Adrenergic Agonists
Clonidine vs. Placebo in DPN
NSAIDS and Coxibs
Extrapolation of data from clinical trials on
analgesic efficacy is problematic
 Most clinical trials emphasize responsiveness of
patients treated for RA or other arthritic
conditions
 Lack of association between anti-inflammatory
and analgesic effects
 Lack of toxicity data in young, healthy subjects
using NSAIDS solely for pain
 Analgesic response highly variable between
individuals
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Mechanisms of Analgesia
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Analgesia occurs primarily through actions outside the CNS
Inhibition of cyclo-oxygenase and lipoxygenase
Facilitation of descending CNS pathways
Inhibition of peripheral inflammation through non-prostaglandin
CNS mechanisms
Cellular effects – inhibition of inflammatory mediator release from
neutrophils and macrophages
Mechanisms of Analgesia
PHOSPHOLIPID
PHOSPHOLIPASE
CYCLOOXYGENASE
Cox 1 and Cox 2
ARACHIDONIC ACID
CYCLIC ENDOPEROXIDES
PROSTAGLANDINS
PGA
PGD2
PGE2
PGF2α
LIPOXYGENASE
PROSTACYCLINS
THROMBOXANE A2
PGI2
TXA2
Sensitization of nociceptors
5-HPETE
LEUKOTRIENES
5-HETE
LTA
LTB
LTC
LTD
Thermal
hyperalgesia
Characteristics of NSAIDS
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Similar pharmacokinetic profiles
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Rapidly and extensively absorbed
Limited tissue distribution (protein binding)
Metabolized in liver
Significant toxicity profile
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Gastrointestinal (>70%)
 Bleeding
Renal
 Dec. GFR, elevation of BP
 Acute nephritis
Hematologic
 Decrease platelet function
Hepatic (3%)
NSAIDS for Treatment of Chronic LBP
One systematic reviews of 2 studies within
framework of Cochrane Collaboration
 NSAID vs. Placebo
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Better short-term pain relief
NSAID vs. Acetominophen (N=4)
No difference in short-term pain relief
 Better overall improvement
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Corticosteroids
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May be useful in the short term for treatment of radicular
pain
Systemic steroids probably have a limited role in the
long-term treatment of patients with FBSS
Epidural or transforaminal steroids may be useful in
selected patients
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Cochrane Review (Nelemans, et al., 2002)
No significant difference in pain relief after 6 weeks or 6
months between ESI and placebo
Most trials included patients with radicular pain
Systematic Reviews on Conservative
Treatment of Chronic LBP
Review
# Trial
Comparison Results