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

2. 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

3. Drug for Treatment of FBSS • NSAIDS and Coxibs • Corticosteroids • Anti-epileptics • Anti-depressants • Opioids • Topical agents • Miscellaneous drugs

4. 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

5. 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

6. 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

7. 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

8. 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

9. Antidepressant Medications Tricyclic-type ADSSRI-type AD Amitriptyline Fluoxetine Nortriptyline Paroxetine Clomipramine Ritanserin Desipramine Citalopram Impramine Fluvoxemine Doxepin Sertraline Maprotiline Ritanserin SNRI antidepressant Trazadone Venlaflexine Trimipramine

10. 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)

11. Antidepressants for LBP-RCT

12. 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

13. 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

14. 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 (>2000mg) • Withdrawal reactions

15. Adverse Effects of 2nd Generation AEDS

16. 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

17. AEDS Studied in Neuropathic Pain

18. 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

19. 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

20. Gabapentin in PHN

21. Pregabalin for Diabetic Neuropathy

22. Gabapentin in Diabetic Neuropathy

23. Pregabalin for PHN

24. Weak Opioids Codeine Dihydrocodeine Dextropropoxyphene Tramadol Strong Opioids Morphine Methadone Fentanyl Meperidine Oxycodone Buprenorphine Levorphanol Dextromoramide WHO Classification of Opioids

25. Gabapentin vs. Pregabalin

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

27. Bioavailability of Common Opioids Opioid Approximate Bioavailability (%) Hydromorphone 20 Morphine 30 Meperidine 30 Codeine 60 Oxycodone 60 Levorphanol 70 Tramadol 80 Methadone 80

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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)

35. Opioid Therapy - RCT

36. Opioid Therapy – Prospective Uncontrolled Studies

37. Tramadol for LBP

38. 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

39. Equianalgesic Doses of Opiods

40. 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

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

42. Botulinum Toxin for Chronic LBP

43. Botulinum Toxin for Chronic LBPWorld Congress

44. Selection of Neuropathic AnalgesicsGeneral Considerations • Safety • Tolerability • Patient convenience – ease of use • Once daily vs. multiple dosing • Small pills vs. big pills • Effectiveness

45. Topical AgentsLidocaine

46. Lidocaine Patch for LBP

47. Lidocaine Patch for LBP

48. Alpha2 Adrenergic Agonists Clonidine vs. Placebo in DPN

49. 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

50. 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