Richard K. Osenbach, M.D.
Director, Neuroscience Program
Director, Neurosurgical Services
Cape Fear Valley Health System
Fayetteville, NC

 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

 NSAIDS and Coxibs
 Corticosteroids
 Anti-epileptics
 Anti-depressants
 Opioids
 Topical agents
 Miscellaneous drugs

“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

 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
 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
1 st 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

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
 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
Jenkins et al., 1976 Imipramine 50mg
4 weeks
Alcott et al., 1982 Imipramine 150mg
8 weeks
Godkin et al., 1990 Trazadone 200mg
Usha et al., 1996 Fluoxetine 20mg
Elavil 25mg
Placebo
4 weeks
Atkinson et al., 1998 Nortriptyline 100mg
Inert placebo
Dickens et al., 2000 Paroxetine 20mg
No. Effect
44/59 No
Comments
Parallel design
41/50
42
59
57/78
61/92
No Parellel design; poss role for pain
No Parellel design
Serotonergic agent
Yes Parallel design
Fluoxetine more effective with fewer
SE
Yes Parallel design
Non-depressed pts
No Parellel design

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

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

 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 (>2000mg)
 Withdrawal reactions

Adverse Effects of 2 nd Generation AEDS

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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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

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

Weak Opioids
 Codeine
 Dihydrocodeine
 Dextropropoxyphene
 Tramadol
Strong Opioids
 Morphine
 Methadone
 Fentanyl
 Meperidine
 Oxycodone
 Buprenorphine
 Levorphanol
 Dextromoramide

Functional Classification of Opioids
Full Agonists


Morphine
Fentanyl
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Hydromorphone
Codeine
Methadone
Tramadol
Meperidine
Partial Agonists


Buprenorphine
Pentazocine
Agonist-Antagonists
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Nalbuphine
Nalorphine
Antagonists
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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
 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
 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
 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

Implementation of Opioid Therapy
Prerequisites
 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

Implementation of Opioid Therapy
Therapeutic 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

Implementation of Opioid Therapy
Long-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)

Opioid Therapy - RCT
Pain Type Study
Nociceptive Arner & Meyerson, 1988
Kjaersgaard-Anderson, 1990
Neuropathic Arner & Meyerson, 1988
Dellemijn & Vanneste, 1997
Kupers, et al., 1991
Rowbotham et al., 1991
Idiopathic Arner & Meyerson, 1988
Kupers, et al., 1991
Moulin et al., 1996
Unspecified Arkinstall et al., 1995
Mays et al., 1987
Control Results
Placebo Pos
Paracetamol
Placebo
Pos***
Neg
Placebo/Valium Pos
Placebo Pos
Placebo
Placebo
Placebo
Benztropine
Pos
Neg
Neg
Pos***
Placebo Pos***
Placebo/Bupiv Pos

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
Neg
Pos
Gilmann & Lichtigfeld, 1981 Pos
Penn and Paice, 1987
Plummer et al., 1991
Pos
Mixed

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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
Meperidine
Codeine
Dihydrocodeine
Tramadol
Nalbuphine
Oxycodone
Leveorphanol
Hydromorphone
Butorphanol
Oxymorphone
Methadone
Buprenorphine
Equianalgesic Dose
10mg
100
90
60
50
10
7.5
2
2
2
1.5
1
0.3

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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

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

Botulinum Toxin for Chronic LBP
World Congress

Selection of Neuropathic Analgesics
General Considerations
 Safety
 Tolerability
 Patient convenience – ease of use
 Once daily vs. multiple dosing
 Small pills vs. big pills
 Effectiveness

Topical Agents
Lidocaine

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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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
CYCLIC ENDOPEROXIDES ARACHIDONIC ACID
LIPOXYGENASE
5-HPETE
PROSTAGLANDINS PROSTACYCLINS THROMBOXANE A2
PGA
PGD2
PGE2
PGF2
α
PGI2 TXA2
Sensitization of nociceptors
LEUKOTRIENES
LTA
LTB
LTC
LTD
Thermal
5-HETE hyperalgesia

Characteristics of NSAIDS
 Similar pharmacokinetic profiles
 Rapidly and extensively absorbed

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Limited tissue distribution (protein binding)
Metabolized in liver
 Significant toxicity profile
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Gastrointestinal (>70%)
 Bleeding
Renal

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 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
 Better short-term pain relief
NSAID vs. Acetominophen (N=4)
 No difference in short-term pain relief
 Better overall improvement

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

Systematic Reviews on Conservative
Treatment of Chronic LBP
Review # Trial Comparison Results