Chronic Pain Management

1. Chronic Pain Management Beverly Pearce-Smith, MD Clinical Assistant Professor Department of Anesthesiology UPMC-McKeesport Hospital July 2008

2. IASP Definition of Pain “Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.”

3. Acute vs Chronic Pain

4. What is Acute Pain? • Physiologic response to tissue damage • Warning signals damage/danger • Helps locate problem source • Has biologic value as a symptom • Responds to traditional medical model • Life temporarily disrupted (self limiting)

5. What is Chronic Pain? • Chronic pain is persistent or recurrent pain, lasting beyond the usual course of acute illness or injury, or more than 3 - 6 months, and adversely affecting the patient’s well-being • Pain that continues when it should not

6. What is Chronic Pain? • Difficult to diagnose & perplexing to treat • Subjective personal experience • Cannot be measured except by behavior • May originate from a physical source but slowly it “out-shouts” and becomes the disease • It has no biologic value as a symptom • Life permanently disrupted (relentless)

7. Social Consequences Marital/family relations Intimacy/sexual activity Social isolation Socioeconomic Consequences Healthcare costs Disability Lost workdays Domains of Chronic Pain Quality of Life Physical functioning Ability to perform activities of daily living Work Recreation Psychological Morbidity Depression Anxiety, anger Sleep disturbances Loss of self-esteem

8. Nociceptive vs Neuropathic Pain Nociceptive Pain Caused by activity in neural pathways in response to potentially tissue-damaging stimuli Neuropathic Pain Initiated or caused by primary lesion or dysfunction in the nervous system MixedType Caused by a combination of both primary injury and secondary effects CRPS* Postherpeticneuralgia Postoperativepain Trigeminalneuralgia Arthritis Sickle cellcrisis Neuropathic low back pain Mechanicallow back pain Central post-stroke pain Distalpolyneuropathy (eg, diabetic, HIV) Sports/exerciseinjuries *Complex regional pain syndrome

9. Sensations numbness tingling burning paresthetic paroxysmal lancinating electriclike raw skin shooting deep, dull, bonelike ache Signs/Symptoms allodynia: pain from a stimulus that does not normally evoke pain thermal mechanical hyperalgesia: exaggerated response to a normally painful stimulus Possible Descriptions of Neuropathic Pain

10. Transduction Transmission Modulation Perception Interpretation Behavior Physiology of Pain Perception Injury Brain Descending Pathway Dorsal RootGanglion PeripheralNerve AscendingPathways C-Fiber A-beta Fiber Dorsal Horn A-delta Fiber Spinal Cord Adapted with permission from WebMD Scientific American® Medicine. 10

11. Pathophysiology of Neuropathic Pain • Chemical excitation of nonnociceptors • Recruitment of nerves outside of site of injury • Excitotoxicity • Sodium channels • Ectopic discharge • Deafferentation • Central sensitization • maintained by peripheral input • Sympathetic involvement • Antidromic neurogenic inflammation

12. Multiple Pathophysiologies May Be Involved in Neuropathic Pain • More than one mechanism of action likely involved • Neuropathic pain may result from abnormal peripheral nerve function and neural processing of impulses due to abnormal neuronal receptor and mediator activity • Combination of medications may be needed to manage pain: topicals, anticonvulsants, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and opioids • In the future, ability to determine the relationship between the pathophysiology and symptoms/signs may help target therapy

13. Neuropathic Pain • “Pain initiated or caused by a primary lesion or dysfunction in the nervous system” Merskey & Bogduk1994 • Central & peripheral sites • Acute & chronic pain states • CRPS I: consequent of acute, often minor trauma • CRPS II: consequence of nerve injury • Sympathetically maintained Pain (SMP) or independent of the SNS

14. Neuropathic Pain • Burning, stabbing, paraesthesia, allodynia, hyperalgesia • Threshold for activation of injured 1o afferents is lowered • Ectopic discharges may arise from the injury site or the DRG • 2o to changes in Na+ channel expression • Central Sensitisation in the cord • 2o to peripheral inputs • 2o to central changes • Reduced inhibition • Functional (neurotransmitter) & anatomical (sprouting) changes in Aβ fibres  tactile allodynia (pain induced by light touch)

15. Acute Neuropathic Pain • Acute causes • iatrogenic, traumatic, inflammatory, infective • Acute neuropathic pain = 1-3% • Based on cases referred to an acute pain service • Majority still present at 12 months • May be a risk factor for chronic pain • Prompt diagnosis & Rx may prevent chronic pain

16. Examples of Acute NP • Phantom Limb Pain (PLP) • Complex Regional Pain Syndrome (CRPS) • Spinal Cord Injury Pain • Peripheral nerve injury • Post-surgical (eg thoracotomy, mastectomy)

17. NEUROPATHIC PAIN LESION IN THE NERVOUS SYSTEM • EXPERIENCED IN PARTS OF BODY THAT APPEAR NORMAL • CHRONIC • SEVERE • RESISTANT TO OVER THE COUNTER ANALGESICS • AGGRAVATED BY ALLODYNIA

18. Chronic Pain Syndromes • Neuralgias • Causalgia • Complex Regional Pain Syndrome (aka: RSD • Hyperesthesias • Myofascial pain syndromes • Hemiagnosia • Phantom limb pain

19. COMMON TYPES OF NEUROPATHIC PAIN PERIPHERAL CENTRAL Compressive myelopathy from spinal stenosis HIV myelopathy MS Parkinson disease Post ischemic myelopathy Poststroke pain Posttraumatic spinalcord injury • Polyradioculopathy • Alcoholic polyneuropathy • Entrapment neuropathies (carpal tunnel) • Nerve compression by tumor • Diabetic neuropathy • Phantom limb pain • Postherpetic neuralgia • Trigeminal neuralgia

20. CLINICAL EVALUATION OF PTS WITH SUSPECTED NEUROPATHIC PAIN • HISTORY- pain intensity (0 to 10), sensory descriptors, temporal variation, functional impact, attempted treatments, alcohol • PHYSICAL- gross motor, DTRs, skin, sensory-light touch, pin prick, vibration, dynamic /thermal allodynia, hyperalgesia, tinel`s • SPECIAL TESTS- CT, MRI, EMG, nerve conduction, clinical biochemistry

21. NEUROPATHIC PAIN • SPONTANEOUS- CONTINOUS OR INTERMITTENT -Burning, Shooting, Shock-like • STIMULUS EVOKED- ALLODYNIA AND HYPERALGESIA -Extension of allodynia above and below the originally affected dermatomes is a feature of central sensitization.

22. Neuropathic pain arises following nerve injury or dysfunction Gilron, I. et al. CMAJ 2006;175:265-275 Copyright ©2006 Canadian Medical Association or its licensors

23. PATHOPHYSIOLOGY • PERIPHERAL MECHANISMS Peripheral nerve injury 1. Sensitization by spontaneous activity by neuron, lowered threshold for activation, increased response to given stimulus. 2. Formation of ectopic neuronal pacemakers along nerve and increased expression of sodium channels and voltage gated calcium channels. (α 2 delta subunit- where gabapentin acts) 3. Adjacent demyelinated axons can have abnormal electrical connections channels and increased neuronal excitability.

24. PATHOPHYSIOLOGY CENTRAL MECHANISMS Sustained painful stimuli results in spinal sensitization (neurons within dorsal horn) • Increased spontaneous activity of dorsal horn neurons, reduced activation thresholds and enhanced responsiveness to synaptic inputs. • Expansion of receptive fields, death of inhibitory interneurons (intrinsic modulatory systems). • Central sensitization mediated by NMDA receptors that further release excitatory amino acids and neuropeptides. • Sprouting of sympathetic efferents into neuromas and dorsal root and ganglion cells.

25. Systemic medications* Pain Treatment Continuum Most invasive Least invasive Continuumnot related to efficacy Psychological/physical approaches Topical medications Interventional techniques* *Consider referral if previous treatments were unsuccessful.

26. Nonpharmacologic Options • Biofeedback • Relaxation therapy • Physical and occupational therapy • Cognitive/behavioral strategies • meditation; guided imagery • Acupuncture • Transcutaneous electrical nerve stimulation

27. Pharmacologic Treatment Options • Classes of agents with efficacy demonstrated in multiple, randomized, controlled trials for neuropathic pain • topical analgesics (capsaicin, lidocaine patch 5%) • anticonvulsants (gabapentin, lamotrigine, pregabalin) • antidepressants (nortriptyline, desipramine) • opioids (oxycodone, tramadol) • Consider safety and tolerability when initiating treatment

28. FDA-Approved Treatments for Neuropathic Pain • Carbamazepine • trigeminal neuralgia • Duloxetine • peripheral diabetic neuropathy • Gabapentin • postherpetic neuralgia • Lidocaine Patch 5% • postherpetic neuralgia • Pregabalin* • peripheral diabetic neuropathy • postherpetic neuralgia *Availability pending based upon controlled substance scheduling by the DEA.

29. Pharmacologic Agents Affect Pain Differently Descending Modulation BRAIN Anticonvulsants Opioids Tricyclic/SNRI Antidepressants Spinal Cord CNS Dorsal Horn Central Sensitization PNS Anticonvulsants Opioids NMDA-Receptor Antagonists Tricyclic/SNRI Antidepressants Peripheral Sensitization Local Anesthetics Topical Analgesics Anticonvulsants Tricyclic Antidepressants Opioids

30. Postherpetic neuralgia gabapentin* pregabalin * Diabetic neuropathy carbamazepine phenytoin gabapentin lamotrigine pregabalin * HIV-associated neuropathy lamotrigine Trigeminal neuralgia carbamazepine* lamotrigine oxcarbazepine Central poststroke pain lamotrigine Anticonvulsant Drugs for Neuropathic Pain Disorders *Approved by FDA for this use. HIV = human immunodeficiency virus.

31. Gabapentin in Neuropathic Pain Disorders • FDA approved for postherpetic neuralgia • Anticonvulsant: uncertain mechanism • Limited intestinal absorption • Usually well tolerated; serious adverse effects rare • dizziness and sedation can occur • No significant drug interactions • Peak time: 2 to 3 h; elimination half-life: 5 to 7 h • Usual dosage range for neuropathic pain up to 3,600 mg/d (tid–qid)* *Not approved by FDA for this use.

32. Gabapentin • Action:  NT release from hyper-excited neurones • variable oral absorption, no interactions, completely renally excreted • Indication: • Protective analgesia • Neuropathic pain treatment (NNT = 4.7) • SE: sedation, dizziness, ataxia, tremor • NNH minor = 4, NNH major =12-18 • COST! • Doses: • Pre-op: 600-1200mg (1-2 hours pre-op) • Post-op “prophylaxis”: 100-300mg TDS (? 2 weeks) • Post-op “treatment”: 100-900mg TDS (usu 300-600mg tds) Dahl JB, Mathiesen O, Moiniche S. ‘Protective premedication’: an option with gabapentin and related drugs? A review of gabapentin and pregabalin in the treatment of post-operative pain. Acta Anaesthesiol Scand 2004; 48: 1130—1136 Hurley RW, Cohen SP, Williams KA, Rowlingson AJ, Wu CL. The Analgesic Effects of Perioperative Gabapentin on Postoperative Pain: A Meta-Analysis. Reg Anesth Pain Med 2006;31:237-247.

33. Pregabalin • Very similar to gabapentin • More reliable oral absorption • Slightly different side effect profile • Doses: 75-300mg BD

34. Other Anticonvulsants • Effective (NNT 2-3) but less “user friendly” • Most have uncommon but serious SE (eg. aplastic anaemia, hepatotoxicity, Stevens-Johnson syndrome etc) • NNH minor = 3, NNH major = 16 - 24 • Consider • Carbamazepine 100mg BD ( to 400mg bd/tds) • Valproate 200mg BD ( to 1000-2000mg/d) • Phenytoin 100mg nocte ( to 500mg/d) Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathic pain treatment: An evidence based proposal. Pain 118 (2005) 289–305

35. Topical vs Transdermal Drug Delivery Systems

36. Lidocaine Patch 5% • Lidocaine 5% in pliable patch • Up to 3 patches applied once daily directly over painful site • 12 h on, 12 h off (FDA-approved label) • recently published data indicate 4 patches (18–24 h) safe • Efficacy demonstrated in 3 randomized controlled trials on postherpetic neuralgia • Drug interactions and systemic side effects unlikely • most common side effect: application-site sensitivity • Clinically insignificant serum lidocaine levels • Mechanical barrier decreases allodynia

37. Lidocaine • Action: Na+ channel block • Indication: peripheral NP, ? others • Useful IV or topical (NNT = 4.4) • No reliable oral equivalent (mexiletine NNT = 10) • SE: similar rates to placebo for sedation, N/V, pruritis etc • CNS toxicity at plasma levels > 5 mcg/ml • Dose: IV 1-2 mg/kg/hr (??duration) • Patches available in USA, ?EMLA here Challapalli V, Tremont-Lukats IW, McNicol ED, Lau J, Carr DB. Systemic administration of local anesthetic agents to relieve neuropathic pain. Cochrane Database of Systematic Reviews 2005, Issue 4.

38. Ketamine • Action: NMDA receptor antagonist • ‘anti-hyperalgesic', 'anti-allodynic' and 'tolerance-protective' agent • Indication: Protective analgesia, NP treatment, opioid-tolerant patients • SE: Dysphoria, nightmares, “psychedelic” effects • Dose: Low doses usually well tolerated • Intra-op: 0.5mg/kg bolus then 0.25-0.5 mg/kg/hr (beware prolonged recovery) • Post-op: 0.1-0.2 mg/kg/hr (?duration) Himmelseher S, Durieux ME. Ketamine for Perioperative Pain Management. Anesthesiology 2005; 102:211–20 Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine. Acute Pain Management: Scientific Evidence, 2nd Ed. Australian and New Zealand College of Anaesthetists, Melbourne, Australia, 2005; 143-144

39. Principles of Opioid Therapy for Neuropathic Pain • Opioids should be titrated for therapeutic efficacy versus AEs • Fixed-dose regimens generally preferred over prn regimens • Document treatment plan and outcomes • Consider use of opioid written care agreement • Opioids can be effective in neuropathic pain • Most opioid AEs controlled with appropriate specific management (eg, prophylactic bowel regimen, use of stimulants) • Understand distinction between addiction, tolerance, physical dependence, and pseudoaddiction

40. Opioids • A select group of pain patients benefits from opioids, with resultant pain reduction and improved physical and psychological functioning • They have minimal side effects & show increased activity levels & less pain • Other patients do poorly with opioids, experiencing tolerance and side effects, especially with escalating doses

41. Distinguishing Dependence, Tolerance, and Addiction • Physical dependence: withdrawal syndrome arises if drug discontinued, dose substantially reduced,or antagonist administered • Tolerance: greater amount of drug needed to maintain therapeutic effect, or loss of effect over time • Pseudoaddiction: behavior suggestive of addiction; caused by undertreatment of pain • Addiction (psychological dependence): psychiatric disorder characterized by continued compulsive use of substance despite harm

42. Opioids • Action:  NT release,  cell excitability • Indications: Any NP • Oxycodone, morphine (NNT = 2.5) • Tramadol (NNT = 3.9) • SE: usual, and ?OIH • Doses: usual • ? Stay below 100-200mg/d PO Morphine equivalent (ie. 30-60mg/d IV) • ? methadone & buprenorphine less hyperalgesic Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathic pain treatment: An evidence based proposal. Pain 118 (2005) 289–305

43. Antidepressants in Neuropathic Pain Disorders* • Multiple mechanisms of action • Randomized controlled trials and meta-analyses demonstrate benefit of tricyclic antidepressants (especially amitriptyline, nortriptyline, desipramine) for postherpetic neuralgia and diabetic neuropathy • Onset of analgesia variable • analgesic effects independent of antidepressant activity • Improvements in insomnia, anxiety, depression • Desipramine and nortriptyline have fewer adverse effects *Not approved by FDA for this use.

44. Commonly reported AEs (generally anticholinergic): blurred vision cognitive changes constipation dry mouth orthostatic hypotension sedation sexual dysfunction tachycardia urinary retention Desipramine Nortriptyline Imipramine Doxepin Amitriptyline Tricyclic Antidepressants: Adverse Effects FewestAEs Most AEs AEs = adverse effects.

45. Tricyclic Antidepressants • Action: Mixed ( 5-HT &/ Norad at synapse) • Indication: • All NP treatment (except SCI, PLP, HIV) • NNT: overall = 3.1, central = 4.0, periph = 2.3 • PHN prevention: 50%  if used for 90days • SE: dizzy, sedation, anticholinergic • NNH minor = 5, NNH major = 16 • Doses • Amitriptylline 10-25mg nocte, max 100mg • Nortriptylline (?less sedating) same doses Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathic pain treatment: An evidence based proposal. Pain 118 (2005) 289–305

46. Venlafaxine • Action: SNRI • Indication: • mastectomy pain prophylaxis, • peripheral NP treatment (NNT=5.5) • SE: sedation/insomnia, ataxia, BP, nausea • NNH major = not significant • Doses • Protective 75mg/d (pre-op then for 2wks) • Treatment: 37.5-375mg/d Reuben SS, Makari-Judson G, Lurie SD. Evaluation of efficacy of the perioperative administration of venlafaxine XR in the prevention of postmastectomy pain syndrome. J Pain Symptom Manage. 2004; 27: 133-39.

47. Calcitonin • Action: uncertain • Indication: PLP, CRPS, ?other NP • SE: N/V, flushing, dizzy, allergy • Skin prick test advised • Dose: 100 IU in 100ml saline over 1hr • Pre-treat with anti-emetics • Repeat daily for 3 days Visser EJ. A review of calcitonin and its use in the treatment of acute pain. Acute Pain 2005;7 :185-189.

48. Interventional Treatments for Neuropathic Pain • Neural blockade • sympathetic blocks for CRPS-I and II (reflex sympathetic dystrophy and causalgia) • Neurolytic techniques • alcohol or phenol neurolysis • pulse radio frequency • Stimulatory techniques • spinal cord stimulation • peripheral nerve stimulation • Medication pumps CRPS = complex regional pain syndrome.

49. Summary of Advances in Treatments for Neuropathic Pain* • Botulinum toxin: low back pain • Lidocaine patch 5%: low back pain, osteoarthritis, diabetic and HIV-related neuropathy, with gabapentin • CR oxycodone: diabetic neuropathy • Gabapentin: HIV-related neuropathy, diabetic peripheral neuropathy, others • Levetiracetam: neuropathic pain and migraine • Oxcarbazepine: neuropathic pain; diabetic neuropathy • Bupropion: neuropathic pain • Transdermal fentanyl: low back pain *Applications not approved by FDA.

50. CURRENT MANAGEMENT NON PHARMACOLOGIC • EXERCISE • TENS • PENS • GRADED MOTOR IMAGERY • CBT