Pharmacological Management for Failed Back Surgery Syndrome

1
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

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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

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Antidepressant AnalgesicsMerskey 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

• Endorphin link from PAG to pontine raphe nuclei
• Serotonergic conection to spinal dorsal horn
• Noradrenergic pathway from locus ceruleus to
  dorsal horn

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Antidepressant AnalgesicsPharmacology

• 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

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Antidepressant AnalgesicsCurrent Evidence

• 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

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Antidepressant Medications

• Tricyclic-type AD SSRI-type AD
• Amitriptyline Fluoxetine
• Nortriptyline Paroxetine
• Clomipramine Ritanserin
• Desipramine Citalopram
• Impramine Fluvoxemine
• Doxepin Sertraline
• Maprotiline
• Ritanserin SNRI antidepressant
• Trazadone Venlaflexine
• Trimipramine

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AntidepressantsMechanism of Action

• 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)

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Antidepressants for LBP-RCT
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Antidepressants in Neuropathic Pain-RCT

• Watson et al. reviewed 29 randomized clinical
  trials
• 16 involved PHN or PDN
• Mixed SN agents 18/21 (86) Positive effects
• Amitriptyline 10/13, Imipramine 5/5,Doxepin 1/1,
  Venlafexline 2/2
• Noradrenergic agents 10/12 (83) Positive
  effects
• Nortriptyline 3/4, desipramine 4/5, maprotiline
  2/2, bupropion 1/1
• Serotonergic agents 4/5 (80) Positive effects
• Paroxetine 1/2, clomipramine 2/2, citalopram 1/1

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Guidelines for Use of Antidepressants in Pain
Management

• 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

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Adverse Effect of Antidepressants

• Anti-cholinergic autonomic effects (TCAs)
• Allergic and hypresensitivity reactions
• Cardiovascular effects
• Orthostatic hypotension (avoid imipramine in
  elderly)
• Quinidine-like cardiac effects
• CNS effects
• Sedation, tremor, seizures, atropine-like
  delerium, exacerbation of schizophrenia/mania
• Acute overdose may be fatal (gt2000mg)
• Withdrawal reactions

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Adverse Effects of 2nd Generation AEDS
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Anticonvulsant Agents (AEDS)

• 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

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AEDS Studied in Neuropathic Pain
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Mechanisms of Selected AEDS

• 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 Ca2 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

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Adverse Effects of AEDS

• Drowsiness and cognitive dysfunction
• Weight changes
• Weight gain gabapentin
• Weight loss topiramate, zonisamide
• Visual side effects
• Angle closure glaucoma topiramate
• Hallucinations - zonisamide

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Gabapentin in PHN
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Pregabalin for Diabetic Neuropathy
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Gabapentin in Diabetic Neuropathy
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Pregabalin for PHN
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WHO Classification of Opioids

• Weak Opioids
• Codeine
• Dihydrocodeine
• Dextropropoxyphene
• Tramadol

• Strong Opioids
• Morphine
• Methadone
• Fentanyl
• Meperidine
• Oxycodone
• Buprenorphine
• Levorphanol
• Dextromoramide

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Gabapentin vs. Pregabalin
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Functional Classification of Opioids

• Full Agonists
• Morphine
• Fentanyl
• Hydromorphone
• Codeine
• Methadone
• Tramadol
• Meperidine
• Partial Agonists
• Buprenorphine
• Pentazocine

• Agonist-Antagonists
• Nalbuphine
• Nalorphine
• Antagonists
• Naloxone
• Naltrexone

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Bioavailability of Common Opioids

• Opioid Approximate Bioavailability ()
• Hydromorphone 20
• Morphine 30
• Meperidine 30
• Codeine 60
• Oxycodone 60
• Levorphanol 70
• Tramadol 80
• Methadone 80

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Adverse Effects of Opioids

• Common Occasional Rare
• Nausea/vomiting Hallucinations Respiratory dep.
• Constipation Myoclonus Seizures
• Urinary retention Mood changes Delerium
• Sedation Anxiety Hyperalgesia
• Cognitive impairment Rigidity Allodynia
• Pruritis Dry mouth
• Gastric stasis
• Bronchoconstriction
• Tolerance, Physical Dependence, Addiction

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Opioids for Chronic Non-Malignant Pain

• 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

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Principles of Opioid Therapy in Chronic
Non-Malignant Pain

• 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

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Principles of Opioid Therapy in Chronic
Non-Malignant Pain

• Identification of realistic goals of treatment
• Evaluate as a whole
• Not necessarily achievable as single parameters
• Opioids should only be viewed as part of a
  multimodality approach to pain management
• 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

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Implementation of Opioid TherapyPrerequisites

• Failure of pain management alternatives
• 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 TherapyTherapeutic
Trial Period

• Appropriate oral or transdermal drug selection
• Long-acting µ-receptor agonist (Methadone)
• 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

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Implementation of Opioid TherapyLong-Term Therapy

• 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)

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Opioid Therapy - RCT
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Opioid Therapy Prospective Uncontrolled Studies
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Tramadol for LBP
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Conclusions

• 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

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Equianalgesic Doses of Opiods
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Cannabinoids

• 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

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Topical Treatments

• Aspirin preparations
• Eg. aspirin in choroform
• Local anesthetics
• Topical 5 lidocaine patch
• EMLA
• Eutectic mixture of local anesthetics
• Capsaicin

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Botulinum Toxin for Chronic LBP
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Botulinum Toxin for Chronic LBPWorld Congress
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Selection of Neuropathic AnalgesicsGeneral
Considerations

• Safety
• Tolerability
• Patient convenience ease of use
• Once daily vs. multiple dosing
• Small pills vs. big pills
• Effectiveness

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Topical AgentsLidocaine
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Lidocaine Patch for LBP
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Lidocaine Patch for LBP
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Alpha2 Adrenergic Agonists
Clonidine vs. Placebo in DPN
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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

• 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

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Mechanisms of Analgesia
PHOSPHOLIPID
PHOSPHOLIPASE
CYCLOOXYGENASE Cox 1 and Cox 2
LIPOXYGENASE
ARACHIDONIC ACID
CYCLIC ENDOPEROXIDES
5-HPETE
PROSTAGLANDINS
PROSTACYCLINS
THROMBOXANE A2
LEUKOTRIENES
5-HETE
LTA LTB LTC LTD
PGA PGD2 PGE2 PGF2a
PGI2
TXA2
Thermal hyperalgesia
Sensitization of nociceptors
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Characteristics of NSAIDS

• Similar pharmacokinetic profiles
• Rapidly and extensively absorbed
• Limited tissue distribution (protein binding)
• Metabolized in liver
• Significant toxicity profile
• Gastrointestinal (gt70)
• Bleeding
• Renal
• Dec. GFR, elevation of BP
• Acute nephritis
• Hematologic
• Decrease platelet function
• Hepatic (3)

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NSAIDS for Treatment of Chronic LBP

• One systematic reviews of 2 studies within
  framework of Cochrane Collaboration
• NSAID vs. Placebo
• Better short-term pain relief
• NSAID vs. Acetominophen (N4)
• No difference in short-term pain relief
• Better overall improvement

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Corticosteroids

• 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
• 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

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Systematic Reviews on Conservative Treatment of
Chronic LBP