1. Multimodal, Mechanism-Based Approaches to Chronic Non-Malignant Pain Pharmacotherapy Daniel Wermeling, Pharm.D. Professor University of Kentucky College of Pharmacy

2. Chronic Pain Types Nociceptive vs Neuropathic Pain Chronic non-malignant pain can have either or both Neuropathic is more common problem Neuropathic pain originates from stimulation and damage to afferent nociceptive nerve fibers, not the receptors Syndrome results from continuous abnormal processing of sensory input and subsequent physiologic (plasticity) changes within the nervous system Modulation and transmission functions become dysfunctional

3. Peripheral and Central Sensitization: Mechanisms of Chronic Neuropathic Pain

4. Post-Injury Afferent Nerve Changes Some nerves degenerate and the lesions trigger – Expression of Na+ channels on damaged C-fibers – Expression of Na+, α-adrenoceptor on uninjured fibers – Promotes hyperexcitation and spontaneous nerve firing

5. Ca 2+ Glutamate C-Fiber Central Axon AMPA NMDA Substance P NK-I Na + K+K+ Ca2 + Mg2 + Plug Removed c-fos expression NO Synthase NO PKC Dorsal Horn Cell GABA B μ δ α2α2 5-HT 3 Baclofen Opioids Clonidine GABAA 5-HT1B K+K+ Guanyl Synthase Closed K + Channel Sensitization Acute to Chronic Continuum Basbaum A. PNAS. 1999;96:7739-7743.

6. Neuropathic Pain Sensations Allodynia - Painful response to a non-noxious stimulus (rubbed by a feather) Hyperalgesia – exaggerated painful perception to normally noxious stimulus (like a pin-prick) Burning (like foot on a hot plate) Tingling Electrical shock, shooting Closest example of “hitting your funny bone” Disability is high because of pain symptoms

7. Painful Peripheral Neuropathies Focal/multifocal – Entrapment – Phantom limb/stump – Post-trauma – Post-herpetic – Diabetic – Ischemic Generalized (poly) – Diabetes – Alcohol/toxins/drugs – HIV – Amyloidosis – Vit B deficiency – Hypothyroidism

8. Other Painful Lesions Lesions of CNS – Spinal cord injury – Brain infarction (thalamus and brainstem) – Spinal infarction – Multiple sclerosis Complex Regional Pain Syndromes or reflex sympathetic dystrophy (RSD) – Type 1 – noxious event to tissues, like trauma – Type 2 – peripheral nerve/root injury, brachial plexus – Sympathetic nervous system also damaged

9. Impact of Chronic Pain on the Dimensions of Quality of Life Pain Physical Functional ability Strength/fatigue Sleep and rest Nausea Appetite Constipation Social Caregiver burden Roles and relationships Affection/sexual function Appearance Psychological Anxiety Depression Enjoyment/leisure Pain distress Happiness Fear Cognition/attention Spiritual Suffering Meaning of pain Religiosity Adapted from Ferrell et al. Oncol Nurs Forum. 1991;18:1303–9.

10. The Terrible Triad of Chronic Pain Chronic Pain Sleeplessness Suffering Sadness National Institute of Neurological Disorders and Stroke, 1989.

11. Neuropathic Pain: First-Line Pharmacotherapy Supported by good evidence – Alpha-2-delta nerve modulators: Gabapentin* and Pregabalin* – Antidepressants: TCAs* and duloxetine* – Carbamazepine for TN* – Lidocaine patch 5%* – Opioid analgesics, including tramadol *FDA-approved for the treatment of postherpetic neuralgia. † Not FDA-approved for analgesia. Carbamazepine: FDA-approved for trigeminal neuralgia. ‡ FDA-approved for the treatment of painful diabetic neuropathy. 1. Dworkin RH et al. Arch Neurol. 2003;60:1524-1534. 2. FDA news, 2004. Available at: http://www.fda.gov/bbs/topics/news/ 2004/NEW01113.html. Accessed March 29, 2006. 3. Lesser H et al. Neurology. 2004;63:2104-2110.

12. Neuropathic Pain Other commercially-available treatments – Other AEDs Topiramate, oxcarbazepine, levetiracetam, zonisamide, tiagabine – Other ADs SNRI (venlafaxine), SSRI (paroxetine, citalopram), others (maprotiline, bupropion)

13. Neuropathic Pain Other commercially-available treatments – Alpha-2 adrenergic agonists Tizanidine, clonidine – NMDA antagonists Ketamine, memantine – Other sodium channel blockers Mexiletine, tocainide, flecainide – Cannabinoids THC, nabilone

14. Linkage of Symptom to Treatment SymptomPathol. Process TargetsMech. Of Action Options Spontane ous Shooting Pain Ectopic nerve impulse Sodium Channel Selective Sodium Channel Blocker TCAs Topical Lidocaine

15. SNRIs for Treatment of Neuropathy

16. Treatment of Depression and Pain

17. Tramadol/Tapentadol Central analgesic MOA – weak mu receptor agonist and weak NE and SE reuptake inhibition Synergy between mechanisms Useful in neuropathic pain Start low and increase dose to tolerance Dizziness, vertigo, GI, headache Avoid use in seizure risk patient Abuse liability and recently a controlled substance in KY

18. Antianxiety Agents In chronic pain, benzodiazepines can relieve pain by reducing anxiety associated with the chronic pain state and resulting insomnia and muscle tension Also used as anticonvulsants and antispasmodics for neuropathic pain Adverse effects: cognitive impairment, physical dependence, worsen depression, additive CNS depressant effects when combined with opioid

19. Skeletal Muscle Relaxants Agents include baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, diazepam, metaxalone, methocarbamol, orphenadrine, tizanidine Beneficial for pain states involving muscle spasm Interrupt pain-spasm-pain cycle Improve range of motion, help patients regain function, facilitates rehab and therapeutic exercise Adverse effects: Drowsiness, dizziness, light- headedness, fatigue, sedation

20. Corticosteroids Powerful anti-inflammatory agents that reduce nociception Often used for tumor-related pain Variety of adverse effects from systemic administration; should be limited to 1 to 2 weeks of therapy Injections widely used for tendonitis, bursitis, tenosynovitis, epicondylitis

21. Botulinum Toxins Neurotoxins block acetylcholine release at neuromuscular synapses, causing paralysis May also have independent analgesic effects – Anti-inflammatory, blocking release of glutamate, reducing concentrations of substance P Demonstrated efficacy – In myoclonus, tension-type headache, trigger points, myofascial pain, back pain, cervical dystonia and other focal dystonias, and spastic disease states Usually reserved for refractory cases

22. Data Collection and Assessment Standard assessment protocol required – Have patient describe their pain through structured interview. How does it affect daily living? – Physical examination and history – Supportive tests, labs, radiology, nerve conduction – Psychological and Social assessment – Rule out treatable causes of pain, establish diagnosis – Begin pharmacotherapy protocols based on symptoms – Substance abuse history – Medication History – Goal is to improve daily function and quality of life

23. General Approach to Pharmacologic Treatment Nociceptive pain, acute pain, is easy to treat with conventional pharmacologic agents Chronic pain is not acute pain that persists Treating chronic pain with acute pain models will have poor outcomes Neuropathic pain is not easily treated with conventional analgesics and requires a multimodal approach There can be a nociceptive component Most effective agents affect nerve transmission

24. General Neuropathic Pain Pharmacotherapy Tricyclic antidepressants, such as amitriptyline, or anti-epileptic drugs, such as gabapentin or pregabalin are drugs of choice Topical products such as lidocaine and capsaicin for certain focal neuropathy Opioids can be adjuncts but must be used at much higher doses than nociceptive pain – big risks for little benefit in general Some patients receive nerve blocks, spinal cord stimulators (Jerry Lewis), &/or IT delivery

25. General Considerations Oral conservative therapy is first line Titrate upward for trials with each medication Additional medications to be added General outlines “work” for back, diabetic, and other neuralgias Herpetic neuralgia responds to topical capsaisin and lidocaine patch Multimodal therapy may advance to IT delivery with opiates, clonidine, ziconotide

26. Finnerup, Pain 2005 Simplistic Algorithm for Peripheral Neuropathic Pain

27. Or Capsaicin Cream

28. Reassessment is Critical Was the medication successful in reducing any pain or to some meaningful degree? – What is meaningful? Expectations? – ? 50% reduction in pain score ? – Do they feel better or worse? – Can they do more than they used to? – Document the improvement – Discontinue if no benefit!! – Too many patients on cocktails Add another medication for a trial and repeat

29. Opioids for CNMP Consensus statement, American Academy of Pain Must alleviate under-treated pain and suffering Places much greater emphasis on thorough patient assessments and frequent evaluations, creating treatment plans and documenting effects Individualized treatment plans Written agreements (contracts) with patients Functional improvement outcomes must be overall goal

30. Dependence-Producing Agents in Chronic Pain: Basic Principles First line use for breakthrough CNP episodes Replace with non-narcotic as soon as possible Chronic therapy – Use SR opioids, or – Methadone, since it has dual action at NMDA receptor In general use these agents with caution: – Potential for abuse is great – Patients use as a shortcut to controlled physical activities – Detoxification may be necessary at some point to achieve optimal analgesia. Well-defined, short-term therapy is essential

31. Mayer 2007, Erickson Pain 2007 Long-term Opioid Use Linked to Worse Outcome After Back Injury Opioid Dependence Risk is Great and Results in – Longer disability (29 vs 17months) – 2.5 x more likely to have surgery – 2.5 x more likely to have antisocial disorder – 2 x more likely to have had pre-injury substance use disorder – 2 x more likely to have depressive or anxiety disorder – 90% still have moderate to severe pain

32. Low Back Pain: Nociceptive vs Neuropathic Pain 1. International Association for the Study of Pain. IASP pain terminology. Available at: http://www.iasp-pain.org/terms-p.html# Neuropathic%20pain. Accessed March 9, 2006. 2. Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice. Philadephia, Pa: FA Davis Co; 1996:248-276. 3. NPC/JCAHO. Pain: Current Understanding of Assessment, Management, and Treatments. December 2001. Nociceptive Caused by activity in neural pathways in response to stimuli potentially damaging to tissue Responsive to analgesics Neuropathic Initiated or caused by primary lesion or dysfunction in the nervous system Responsive to neuromodulators May require poly- pharmacotherapy Mixed Caused by both primary injury and secondary effects May require poly- pharmacotherapy

33. Pharmacological Treatment Options for Low Back Pain Nonspecific analgesics – NSAIDs – Opioids – “Muscle relaxants” – Analgesic antidepressants TCAs SNRIs Others – Alpha-2 adrenergic agonists Tizanidine – Topical LA For neuropathic pain – All nonspecific drugs – AEDs – Others

34. Interventional Treatment Options for Low Back Pain Injection therapies – Epidural steroid injections – Facet steroid injections – Botulinum toxin injection Neural blockade – Radiofrequency median branch block Implant therapies – Spinal Cord Stimlators – Neuraxial infusion

35. Nonpharmacologic Treatment Options for Low Back Pain Physical medicine approaches Psychological approaches Lifestyle changes

36. Conclusion CNMP is a difficult, common medical problem Treatment is complex and multimodal Pharmacotherapy approaches are complex and use medications alone and in combination Off-label drug prescribing is common

37. Conclusions Screen and assess patients for pain complaints Monitor and document findings to protect the patient, society and medical and pharmacy clinicians Modify to decrease pain symptom and associated morbidity Omnibus goal – Promote optimal functional living

38. Pharmacists Have an Obligation to Relieve Pain “I will consider the welfare of humanity and relief of human suffering my primary concerns.” Oath of a Pharmacist