Front Line Pain Management: Evidencebased non-opioid pharmacotherapy for the treatment of common neuropathic pain syndromes

Transcription

1 Front Line Pain Management: Evidencebased non-opioid pharmacotherapy for the treatment of common neuropathic pain syndromes Shane Donnelly, PharmD, BCGP Delta Care Rx Clinical Pharmacist

2 Disclosures No financial disclosures or conflicts of interest Off-label use of medication will be discussed

3 Learning Objectives 1. Describe the pathophysiology of pain as it pertains to neuropathic versus nociceptive pain 2. Employ evidence-based pain assessment techniques to identify neuropathic pain 3. Recall adjuvant and coanalgesic pharmacotherapy utilized for the treatment of neuropathic pain 4. Devise evidence-based recommendations for non-opioid pharmacotherapy to treat common neuropathic pain syndromes

4 Purpose 2012 NIH survey reports 11.2% of U.S. adults experience daily pain More than 11.5 million Americans (12 years of age or older) reported misusing prescription opioids in : 165,000 people in the U.S. died from prescription opioids Up to 10 % of the global population may be suffering from chronic neuropathic pain J Pain 2015;16: CDC.2018 Annual Surveillance Report of Drug-Related Risks and Outcomes United States. Surveillance Special Report 2. CDC; 2018 CDC. Multiple cause of death data on CDC WONDER. Atlanta, GA: US Department of Health and Human Services, CDC; 2016

5 WHO Analgesic Ladder Step 2: Step 3: Opioid for moderate-severe pain ± Nonopioid analgesic ± Adjuvant analgesic Step 1: Opioid for mild-moderate pain ± Nonopioid analgesic ± Adjuvant analgesic Nonopioid analgesic ± Adjuvant Increasing pain Increasing pain

6 Describe the pathophysiology of pain as it pertains to neuropathic versus nociceptive pain

7 J Neurol. 2018; 265(2): Pathophysiology of Pain Body is equipped with different types of sensory neurons Mechanoreceptors Thermoreceptors Chemoreceptors Nociceptors Nociceptors: Sensory neurons that function primarily to perceive pain Nociception: Encoding of noxious stimuli that can cause tissue damage

8 Pathophysiology of Neuropathic Pain Lesions or disease of somatosensory pathways lead to loss of function and paradoxically increased pain sensitivity and spontaneous pain Highly variable etiology Infection Toxins Spinal cord compression/entrapment Serves no protective function Primarily chronic in nature J Neurol. 2018; 265(2):

9 Classification of Neuropathic Pain Central neuropathic pain involves neuropathic pain associated with the spinal cord or brain Examples include: Spinal Cord injury Post-stroke neuropathy Multiple sclerosis neuropathic pain CNS malignancy Pain Jan;160(1):53-59

10 Classification of Neuropathic Pain Peripheral neuropathic pain involves neuropathic pain associated with damage to the peripheral somatosensory system Examples include: Chemotherapy-induced PN Diabetic PN Trigeminal neuralgia Postherpetic neuralgia Pain Jan;160(1):53-59

11 Case Study #1 KB is a 46 year old male who presents to your community pharmacy with a sullen look on his face. He confided in you several months ago that he was diagnosed with stage 4 lung cancer. He s been undergoing chemotherapy and has been receiving high doses of morphine and fentanyl to manage his pain, yet his pain still seems to be unmanaged as evidenced by early refill requests for his short acting opioid, reports from close family members, and the non-verbal indicators of pain that you notice when you re counseling him on his new prescription for duloxetine. You then ask him about his pain and he describes it as intermittent stabbing, shooting pain that runs down the length of his right leg. He also states that he feels a dull, achy pain on the right side of his abdomen. He rates his pain a 9/10 on average, with 7/10 being the lowest and 10/10 being the highest.

12 Question #1: Which of the following neuropathic pain pathologies is plausible for KB? a. Toxic (chemotherapy-induced) b. Trigeminal neuralgia c. Neoplastic d. Degenerative e. A and C f. B and C g. None of the above

13 Employ evidence-based pain assessment techniques to identify neuropathic pain

14 Principles of Pain Assessment for Pharmacists Identify characteristics of pain Determine potential mechanism(s) of pain Clarify precipitating and palliating factors Understand patient-centric goals of care Referral, monitoring, and follow-up J Clin Oncol Jun 1; 32(16):

15 Principles of Pain Assessment for Pharmacists Patient interview Medical history Onset Location(s) Intensity Severity Level of disability Impact on sleep and quality of life PQRSTU method Pain Jan;152(1):14-27 J Clin Oncol Jun 1; 32(16):

16 Pain Assessment- Differentiation of Pain Types Type of Pain Quality Description Features Examples Nociceptive-Somatic (musculoskeletal) Throbbing, aching, stabbing, squeezing, dull Easily located Inflammation very common Worsened by movement Bone Metastases Wounds Joint pain Nociceptive-Visceral (organ and deep tissue) Sharp, throbbing, cramping, gnawing, aching Hard to locate Inflammation common Angina Irritable bowel syndrome Referred pain Neuropathic (CNS and PNS) Electrocuting, pins and needles, burning, shooting, itchy, tingling, numbness Radiation along areas of nerve innervation Travels down or.. across Postherpetic neuralgia Diabetic neuropathy J Clin Oncol Jun 1; 32(16):

17 Pain Assessment- Severity On a scale of 0 to 10, how would you rate your pain today? Gold standard for pain assessment in verbal cancer patients Three commonly-used modalities: Visual analogue scale (VAS) mm Numeric rating scale Pain on a scale of 0-10 Categorical scale Mild, moderate, or severe Pay attention to time frame J Natl Compr Canc Netw. 2010;8:

18 Neuropathic Pain Assessment for Pharmacists Patient interview may suggest nociceptive, neuropathic, or mixed pain modality Validated screening tools available if needed Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) Douleur neuropathique en 4 questions (DN-4) Neuropathic Pain Questionnaire (NPQ) Patient interview alone may suffice Pain Jan;152(1):14-27

19 Neuropathic Pain Questionnaire 0 No Pain 100 Worst Pain Total Discriminant Function Score: Below 0 = Predicts non-neuropathic pain At or above 0 = Predicts neuropathic pain 1. Burning Pain Rating: x = 2. Overly Sensitive to Touch Rating: x = 3. Shooting Pain Rating: x = 4. Numbness Rating: x = 5. Electric Pain Rating: x = 6. Tingling Pain Rating: x = Clin J Pain Sep-Oct;19(5):306-14

20 NeuPSIG Neuropathic Pain Algorithm Possible neuropathic pain as evidenced by pain along the pathway of nerve innervation Confirmatory Tests a. Presence of positive or negative sensory symptoms a. Diagnostic test i. ENPG ii. MRI Neither Unconfirmed Both One Definite neuropathic pain Likely neuropathic pain Pain Jan;152(1):14-27

21 Case Study #2 Patient SC is an 83 year old female patient residing in a long-term care facility. Her past medical history includes CAD, CHF, CVD, HTN, COPD, DM2, and CKD 4. She is cognitively intact. You are reviewing her medication list and notice that the attending physician initiated gabapentin 3 days ago. Documentation of the indication for the gabapentin is missing from the patient s chart. The current dose of gabapentin is 300 mg PO BID. Concurrent opioid and non-opioid analgesic therapy includes oxycodone 5 mg tablet PO q4h prn pain and acetaminophen 500 mg tablet PO q4h prn pain.

22 Question #2 and 3 What questions do you have for AB to elucidate the potential indication for gabapentin therapy? True or False: This patient may be experiencing both nociceptive and neuropathic pain

23 Recall adjuvant and coanalgesic pharmacotherapy utilized for the treatment of neuropathic pain

24 Gabapentin and Gabapentin Enacarbil Combined NNT = 7.2 (reduce pain score by 30-50%) First line Effective Dose: mg/day Saturable absorption (nonlinear PK) Renal dosing (eliminated as 100 % unchanged drug via the urine) Opioid sparing Lancet Neurol Feb;14(2): Cochrane Database Syst Rev Jun 9;6:CD007938

25 Pregabalin Combined NNT = 7.7 (reduce pain score by 30-50%) First line Effective dose: mg/day Improved analgesia with escalating doses Renal dosing required (eliminated as 90% unchanged drug via urine) Opioid sparing Lancet Neurol Feb;14(2):162-73

26 SNRI s (duloxetine and venlafaxine) Combined NNT = 6.4 (reduce pain score by 30-50%) First line Venlafaxine Effective dose: 150 mg/day or higher SSRI in low doses (37.5 mg/day), SNRI at higher doses ( 225 mg/day) Duloxetine Effective dose: mg/day Pain Med Oct 1;18(10): J Clin Oncol Jun 20;32(18):

27 Lancet Neurol Feb;14(2): Tricyclic Antidepressants Combined NNT = 3.6 (reduce pain score by 30-50%) First line Preferable to utilize secondary amines versus tertiary amines Similar efficacy between agents Tertiary amines- Higher degree of sedation, anticholinergic side effects Adverse effects pronounced in elderly 75 mg/day max dose of tertiary amines in patients 65 years old

28 Second and Third Line Adjuvant Analgesics Capsaicin 8% patches (not available OTC) Combined NNT = 10.6 (reduce pain score by 30-50%) Dose: 1-4 patches to painful area(s) for mins q3months Peripheral neuropathic pain only Lidocaine patches Dose: 1-3 patches to painful area(s) once a day q12h on and q12h off Peripheral neuropathic pain only Botulinum toxin A Administered subcutaneously units to painful area(s) q3months Peripheral neuropathic pain only Lancet Neurol Feb;14(2):162-73

29 Second and Third Line Adjuvant Analgesics Cannabis Capsaicin cream SSRI s Topiramate Zonisamide Lancet Neurol Feb;14(2):162-73

30 Case Study #3 Patient JT is a 32 year old female who recently moved into the area and is presenting to your primary care clinic. Prior to initial review of her medications and supplements, she states that she suffered from a shingles outbreak in August of She is experiencing pain along the path of the resolved shingles rash, which confuses her and is interfering with her emotional and social well-being. PMH is unremarkable.

31 Question #3 Which of the following adjuvant analgesics would likely be ineffective for treating this patient s neuropathic pain? (Choose all that apply) A. Carbamazepine B. Gabapentin C. Duloxetine D. Topical lidocaine patch E. Escitalopram F. Capsaicin cream G. Imipramine

32 Devise evidence-based recommendations for non-opioid pharmacotherapy to treat common neuropathic pain syndromes

33 Diabetic Peripheral Neuropathy (DPN) 9.4 % of US population diagnosed with diabetes Approximately 30-50% of these patients develop DPN Symptoms include: Pain Numbness Paresthesia First step in managing DPN is glycemic control Ann Intern Med Nov 4;161(9): Diabetes Care. 2005;28: Neurology May 16;88(20):

34 Diabetic Peripheral Neuropathy (DPN) 2017 systematic review concluded the following agents were likely effective for DPN (strength of evidence) Pregabalin (Low) Oxcarbazepine (Low) Duloxetine (Moderate) Venlafaxine (Moderate) TCA s (Low) Botulinum toxin (Low) JAMA 2018 Clinical Evidence Synopsis adds gabapentin to this list Scarcity of head-to-head trials to compare efficacy JAMA. 2018;319(8): Neurology May 16;88(20):

35 Postherpetic Neuralgia (PHN) Three phases of pain associated with herpes zoster infection: Acute- Preceding or accompanying eruption of rash and persists up to 30 days from onset Subacute-Pain that persists beyond healing of rash but resolves within 4 months Postherpetic neuralgia- Pain persisting beyond 90 days from initial onset of rash Debilitating pain that can significantly impact QOL, especially in older adults Pain management strategies should focus on symptom management Some patients have symptom resolution after several years Am Fam Physician Nov 15;96(10): J Pain Jan;9(1 Suppl 1):S37-44

36 Postherpetic Neuralgia (PHN)- Topical Therapy Lidocaine patches 5% patch indicated for PHN Limited evidence of benefit Expensive 4% OTC patch indicated for minor pain Inexpensive Capsaicin 8% patch (not available OTC, $$$$) NNT = 7 (50% reduction in pain) Painful application, pretreat Am Fam Physician Nov 15;96(10):

37 Am Fam Physician Nov 15;96(10): Cochrane Database Syst Rev. 2013;(11):CD Postherpetic Neuralgia (PHN)- Oral Therapy Gabapentin NNT = 8 (50% reduction in pain) mg/day Pregabalin NNT = 4 (50% reduction in pain) 600 mg/day TCA s (amitriptyline, nortriptyline, desipramine) NNT = 3 (50% reduction in pain) No significant differences between agents in terms of efficacy

38 Toxic Neuropathies Neuropathies caused by industrial toxins, heavy metals, drugs, or alcohol Reversal of symptoms typically occurs after stopping offending agent(s) Accurate medication history essential (including OTC supplements [i.e. B6]) Major dose-limiting side effect of commonly-used chemotherapy Curr Opin Neurol Oct;24(5):484-90

39 Pharmacotherapy Associated with Peripheral Neuropathies Chemotherapy Cardiovascular Antimicrobials CNS Agents Miscellaneous Platinum compounds Amiodarone Dapsone Nitrous oxide Colchicine Taxanes Isoniazid Phenelzine Etanercept Thalidomide Linezolid Phenytoin Infliximab Lenalidomide Metronidazole Allopurinol Vinca alkaloids NRTI s Leflunomide 5-FU Fluoroquinolones Sulfasalazine Cytarabine Azoles Gemcitabine Ifosfamide Curr Opin Neurol Oct;24(5):484-90

40 Chemotherapy-Induced Peripheral Neuropathy (CIPN) Lack of high-quality evidence to guide treatment No recommended agents to prevent CIPN Duloxetine (moderate SOE) is only agent recommended for CIPN Evidence is inconclusive for other therapies J Clin Oncol Jun 20;32(18):

41 Pain Pract Mar;12(3): Cancer-related Neuropathic Pain Etiology of cancer pain is typically mixed mechanism Rarely presents as purely nociceptive or neuropathic Often presents at multiple sites with multiple etiologies Inflammatory Neuropathic Ischemic Severity of neuropathic cancer pain follows disease progression Estimated 40 % prevalence of neuropathic pain in patients with cancer

42 Cancer-related Neuropathic Pain Antidepressants and anticonvulsants recommended first line Drug selection may be based off of other symptoms and comorbidities SNRI for concomitant anxiety/depression TCA for concomitant insomnia Trial and error may occur when finding an effective agent for an individual Corticosteroids included as an adjuvant for these patients Usually dexamethasone Useful for acute management of a pain crises J Pain Symptom Manage Oct;46(4):

43 Refractory Cancer-related Neuropathic Pain Lidocaine may be administered intravenously for refractory cancer pain Small studies/case reports support its use for opioid-refractory cancer pain May be able to reduce analgesic requirements Adverse effects include tinnitus, lightheadedness, sedation, and headache Dosing: Bolus: 1-3 mg/kg given over mins Continuously infuse at mg/kg/hr (100 mg/hr max) Clin J Pain Mar-Apr;22(3): J Pain Symptom Manage Jan;37(1):85-93

44 Neuropathic Pain in Multiple Sclerosis Most common inflammatory demyelinating disease of CNS MS-related pain prevalence ranges from 40-86% of patients Often multifactorial Peripheral neuropathies occur in approximately 25% of patients Trigeminal neuralgia occurs in approximately 4% of patients First line pharmacotherapy TCA s, SNRI s, gabapentin, pregabalin (central neuropathic pain) Carbamazepine/oxcarbazepine (trigeminal neuralgia or L hermitte s signs) Pain May;154(5): J Neurol Apr;265(4):

45 Neuropathic Pain in Amyotrophic Lateral Sclerosis Rare neurodegenerative disease with a fatal outcome 2-4 years from onset Pain reported by most patients with ALS Unable to currently support hypothesis that most pain in most patients is neuropathic Pain is largely multifactorial First line pharmacotherapy Gabapentin: mg/day Pregabalin: mg/day TCA s Lancet Neurol. 2017;16(2):144

46 Case Study #4 (Patient from Case Study #1) KB s wife AB walks into your community pharmacy two months after his last visit to the pharmacy. You discuss KB s current situation with his wife and she confides that he is being admitted into hospice services today. Duloxetine had been titrated up to a dose of 90 mg PO once daily without reduction in his pain intensity. Additionally, escalating doses of morphine have not correlated with an increase in pain control. In fact, AB states that the pain just seems to get worse with escalating doses. His pain is currently an 8/10, with the lowest being a 6/10 and highest at a 10/10.

47 Question # 4 What positive sensory feature of neuropathic pain is KB experiencing?

48 Question # 5 Please design a pharmacotherapy care plan aimed at treating this patient s neuropathic pain. This care plan should include: Problem + Current Therapy + Recommendation(s) + Monitoring/Follow Up

49 Questions/Comments?

50 References 1. xnahin, R.. Estimates of Pain Prevalence and Severity in Adults: United States, The Journal of Pain, 2015;16(8): Accessed November 30, xst. John Smith, E.. Advances in understanding nociception and neuropathic pain. Journal of Neurology, 2017;265(2): Accessed November 30, xscholz J, Finnerup NB, Attal N et. al. The IASP classification of chronic pain for ICD-11: chronic neuropathic pain.. Pain. 2019;160(1): Accessed December 2, xhui D, Bruera E. A personalized approach to assessing and managing pain in patients with cancer.. J Clin Oncol. 2014;32(16): Accessed December 2, xxHaanpää M1, Attal N, Backonja M et. al. NeuPSIG guidelines on neuropathic pain assessment.. Pain. 2011;152(1): Accessed December 12, xswarm R, Abernethy AP, Anghelescu DL et. al. Adult cancer pain.. J Natl Compr Canc Netw. 2010;8(9): Accessed December 12, xKrause SJ, Backonja MM. Development of a neuropathic pain questionnaire.. Clin J Pain Sep- Oct;19(5): Accessed December 24th, xFinnerup NB, Attal N, Haroutounian S, et. al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis.. Lancet Neurol Feb;14(2): Accessed December 24th, 2018.

51 9.xWiffen PJ, Derry S, Bell RF, et. al. Gabapentin for chronic neuropathic pain in adults.. Cochrane Database Syst Rev Jun; 9;6:CD Accessed December 28th, xAiyer R, Barkin RL, Bhatia A.. Treatment of Neuropathic Pain with Venlafaxine: A Systematic Review.. Pain Med Oct;18(10): Accessed December 28th, xHershman DL, Lacchetti C, Dworkin RH, et. al. Prevention and management of chemotherapyinduced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline.. J Clin Oncol Jun;32(18): Accessed December 28th, xGriebeler ML, Morey-Vargas OL, Brito JP, et. al. Pharmacologic interventions for painful diabetic neuropathy: An umbrella systematic review and comparative effectiveness network meta-analysis.. Ann Intern Med Nov 4;161(9): Accessed December 28th, xBoulton AJ1, Vinik AI, Arezzo JC, et. al. Diabetic neuropathies: a statement by the American Diabetes Association.. Diabetes Care Apr;28(4): Accessed December 28th, xWaldfogel JM, Nesbit SA, Dy SM. Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life: A systematic review.. Neurology May 16;88(20): Accessed December 28th, 2018.

52 15.xMoore A, Derry S, Wiffen P. Gabapentin for Chronic Neuropathic Pain.. JAMA Feb 27;319(8): Accessed December 31st, xSaguil A, Kane S, Mercado M, Lauters R. Herpes Zoster and Postherpetic Neuralgia: Prevention and Management.. Am Fam Physician Nov 15;96(10): Accessed December 31st, xDworkin RH, Gnann JW Jr, Oaklander AL, et. al. Diagnosis and assessment of pain associated with herpes zoster and postherpetic neuralgia.. J Pain Jan;9(1 Suppl 1):S Accessed December 31st, xWiffen PJ, Derry S, Moore RA, et. al. Antiepileptic drugs for neuropathic pain and fibromyalgia - an overview of Cochrane reviews.. Cochrane Database Syst Rev Nov 11;(11):CD Accessed January 1st, xManji H. Toxic neuropathy. Curr Opin Neurol Oct;24(5): Accessed January 2nd, xVadalouca A, Raptis E, Moka E, et. al. Pharmacological treatment of neuropathic cancer pain: a comprehensive review of the current literature.. Pain Pract Mar;12(3): Accessed January 2nd, Jongen JL, Huijsman ML, Jessurun J. The evidence for pharmacologic treatment of neuropathic cancer pain: beneficial and adverse effects.. J Pain Symptom Manage Oct;46(4): e1. Accessed January 3rd, 2019.

53 22.xTremont-Lukats IW, Hutson PR, Backonja MM. A randomized, double-masked, placebo-controlled pilot trial of extended IV lidocaine infusion for relief of ongoing neuropathic pain.. Clin J Pain Mar- Apr;22(3): Accessed January 4, xSharma S, Rajagopal MR, Palat G, et. al. A phase II pilot study to evaluate use of intravenous lidocaine for opioid-refractory pain in cancer patients.. J Pain Symptom Manage Jan;37(1): Accessed January 4, xFoley PL, Vesterinen HM, Laird BJ, et. al. Prevalence and natural history of pain in adults with multiple sclerosis: systematic review and meta-analysis.. Pain May;154(5): Accessed January 4, xSolaro C, Cella M, Signori A, et. al. Identifying neuropathic pain in patients with multiple sclerosis: a cross-sectional multicenter study using highly specific criteria.. J Neurol Apr;265(4): Accessed January 4, xChiò A, Mora G, Lauria G. Pain in amyotrophic lateral sclerosis.. Lancet Neurol Feb;16(2): Accessed January