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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 Drug for Treatment of FBSS NSAIDS and Coxibs Corticosteroids Anti-epileptics Anti-depressants Opioids Topical agents Miscellaneous drugs 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 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 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 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 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 Watson et al.: reviewed 29 randomized clinical trials 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 16 involved PHN or PDN 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 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 Anti-cholinergic autonomic effects (TCAs) Allergic and hypresensitivity reactions Cardiovascular effects CNS effects 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) 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 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 Weight gain – gabapentin Weight loss – topiramate, zonisamide Visual side effects Angle closure glaucoma – topiramate Hallucinations - zonisamide 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 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 Opioids should only be viewed as part of a multimodality approach to pain management 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 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 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 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 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 Aspirin preparations Local anesthetics Topical 5% lidocaine patch EMLA 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 Once daily vs. multiple dosing Small pills vs. big pills 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 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 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 Similar pharmacokinetic profiles Rapidly and extensively absorbed Limited tissue distribution (protein binding) Metabolized in liver Significant toxicity profile 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 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