Monitoring and Management of Adverse Effects: Adjuvants and Coanalgesics

Monitoring and Management of Adverse Effects: Adjuvants and Coanalgesics Chris Herndon, PharmD, BCPS, CPE

Disclosures  Nothing to Disclose

Learning Objectives  Given a real or simulated patient scenario, develop a complete monitoring plan for commonly used adjuvants and co-analgesics  Select appropriate adjuvant or co-analgesic pharmcotherapy based on patient-specific or disease-specific variables while anticipating side effects of these agents  Identify commonly described drug-drug interactions between the adjuvant and co-analgesic agents and the necessary precautions for prevention

Case Vignette 45 year old female of Asian descent presents for initial evaluation in your outpatient pain service.

PMHx: chronic low back pain, osteoarthritis of the hips, fibromyalgia syndrome, anxiety, and depression  Meds: gabapentin, piroxicam, duloxetine, and hydrocodone / acetaminophen  SHx: + tob 1ppd, + EtOH 1 glass wine, - illicit  FHx: Fa deceased STEMI age 45, Ma alive and well  What monitoring and patient education should be used?

Adjuvant and Co-Analgesics  Nonsteroidal anti-inflammatory drugs (NSAIDs)  Acetaminophen  Corticosteroids  Anti-depressants  Anticonvulsants  Skeletal muscle relaxants  Anesthetics

NSAIDs Non-acetylated salicylates Diflunisal Choline Mg Trisalicylate Salsalate

Propionic acids Ibuprofen Naproxen Ketoprofen Flurbiprofen Oxaprozin

Table adapted from Lexi-Drugs Online. www.uptodate.com. Accessed June 26, 2012.

Acetic acids Diclofenac Etodolac Tolmetin Sulindac Indomethacin Ketorolac

Enolic acids Meloxicam Piroxicam

Other Meclofenamate Mefenamic acid Nabumetone Celecoxib

NSAIDs – Bleeding (GI)  Predominantly COX-1 isoform mediated  Reduction in thromboxane A2 results in decreased platelet aggregation  NSAID induced gastrointestinal bleeding – Minor role, localized epithelial “trapping” – Major role, COX-1 mediated PGE2 mucosal protection from luminal acid and pepsin

 Prostaglandin antibodies produce same gastrointestinal toxicity as nonselective NSAIDs Van Oijen Mg, et al. Clin Gastroenterol Hepatol 2008;6:309-313.

NSAIDs – Bleeding (GI)  COX-2 isoform may mediate GI toxicity – Inhibition of 15-epi lipoxin A4 (lipoxin) – Cytoprotective lipoxin induced during GI injury – CV protective aspirin + COX-2 selective vs. nonselective NSAID?

 Duodenal mucosal injury significantly pH driven – Proposed rationale for H2-antagonist effectiveness Fiorucci S, et al. Gastroenterology 2002;123:1598-1606.

Anonymous. N Engl J Med 1989;321:129-135.

NSAIDs – Bleeding (GI)  Role of Helicobacter pylori undetermined  2 studies show significant differences – Naproxen or diclofenac in H pylori positive pts – Reduction in PUD and UGIB following eradication

 2 studies show no differences between H pylori triple therapy and omeprazole alone Fiorucci S, et al. Gastroenterology 2002;123:1598-1606.

Anonymous. N Engl J Med 1989;321:129-135.

Chan FK, et al. Lancet 1997;350:975-979.

Chan FK, et al. Lancet 2002;359:9-13.

Labenz J, et al. Gut 2002;51:329-335.

Hawkey CJ, et al. Lancet 1998;352:1016-1021.

NSAID induced GI bleed  Risk Factors

– Prior peptic ulcer disease – Prior NSAID GI complication – Advanced age – Concurrent corticosteroid or anticoagulant use – High doses of NSAIDs – Combinations of NSAIDs – ? Combination with SSRI antidepressants

 Prevention

– Eradication of H. Pylori – Proton Pump Inhibitors or Misoprostol

Wilcox CM, et al. Consensus development conference (AGA) on the use of NSAIDs. Clin Gastroenterol Hepatol 2006;4(9):1082-1090..

NSAIDs – Renal Function  Two primary forms of nephrotoxicity – Hemodynamic mediated GFR reduction

• Renal PG synthesis is low outside of glomerular dz, CHF, cirrhosis, and hypovolemia • Little clinical signficance in health patients • Low dose ibuprofen and sulindac appear safest

– Interstitial nephritis and nephrotic syndrome  Renin and aldosterone inhibitory effects – Hyponatremia – Hyperkalemia  Increased risk of renal cell cancer with corresponding decreased risk for several other cancers Huerta C, et al. Am J Kidney Dis 2005;45:531-539.

Patrono C, et al. Kidney Int 1987;32:1-12.

Schneider V, et al. Am J Epidemiol 2006;164:881-889.

NSAIDs – Cardiovascular Risk  American Heart Association (AHA) Advisory

– Naproxen considered safest NSAID – In those with CV disease, non-NSAID or non-acetylated salicylate first

 American College of Rheumatology

– Naproxen likely safest from CV perspective – Lowest dose, shortest duration

 AHA / American College of Cardiology (ACC)HF

– Avoid or stop all NSAIDs in pts with heart failure

 AHA / ACC guidelines on acute MI / ACS

– Immediate cessation of non-aspirin NSAIDs

 Use of naproxen appropriate at discharge if other options unavailable (including non-acetylated salicylates) Antman EM, et al. Circulation 2007;115:1634-1642.

Anonymous. Arthritis Rheum 2008;59:1508-1073.

Antman EM, et al. J Am Coll Cardiol 2008;51:210-247.

Hunt SA, et al. Circulation 2009;119:e391-479

.

AHA Recommendations for acute musculoskeletal pain 1st

• acetaminophen, tramadol • aspirin, short term opioid

• Non-acetylated salicylates

2nd 3rd

• (salsalate, choline magnesium trisalicylate)

• Non-selective NSAIDs • Cox-II Selective NSAIDs

Antman EM. Use of nonsteroidal antiinflammatory drugs. A scientific statement from the American Heart Association. Circulation 2007:DOI: 10.1161/CIRCULATIONAHA.106.181424.

Acetaminophen – Acute Liver Failure  Rapid development of severe acute liver injury with corresponding – Impaired synthetic ability (protein & coagulation factors) – Development of encephalopathy 19% 39% 12%

Acetaminophen Indeterminate Idiosyncratic Viral Hepatitis

13% 17%

Polson J, et al. Hepatology 2005;41:1179.

Ostapowicz G, et al. Ann Intern Med 2002;137:947.

Other

Metabolism

N-acetyl-p-benzoquinone-imine (NAPQI) Glutathione

Sulfate Conjugates

CYP 450

Acetaminophen

Cysteine and Mercaptate Metabolites

Glucuronide Conjugates

Potential drug-drug or drug-dx interactions

Sulfate

CYP 450

Acetaminophen

Conjugates N-acetyl-pbenzoquinoneimine (NAPQI)

Glutathione

 Glucuronidation (UGT 1A6, 1A7, 1A8)  Sulfation  CYP 450 2E1, 1A2, 3A4  Glutathione reduction of NAPQI

Cysteine and Mercaptate Metabolites

Glucuronide Conjugates

What is the dose?  Current standard accepted = 4 gm/day or 1gm / dose  OTC manufacturer = 3 gm/day  American Liver Foundation = 3 gm/day  Avoid or limit use with > 3 drinks / day  Avoid or reduce dose in hepatic disease  Unclear based on FDA Advisory Panel

What is the dose?

N=145; OR 2.78 (1.47-4.09); p< 0.001 Watkins et al. JAMA 2006:296:87-93.

Antidepressants  Tricyclic antidepressants  Selective serotonin reuptake inhibitors  Serotonin / norepinephrine reuptake inhibitors  Atypical antidepressants

Tricyclic Antidepressants (TCAs) Tertiary amines Amitriptyline Imipramine Clomipramine Doxepin Trimipramine

Secondary amines (NE>5HT) Nortriptyline Desipramine Protriptyline

• Secondary amines tolerated better than tertiary amines • Secondary amines equally effective in pain as tertiary amines • Therapeutic drug monitoring of questionable utility

Watson. Neurology 1998;51:1166-1171.

McQuay. Pain 1996;68:217-227.

Table adapted from Lexi-Drugs Online. www.uptodate.com. Accessed June 26, 2012.

TCAs – Cardiovascular Risk  Orthostatic / postural hypotension

– Alpha adrenergic blockade (even at low doses)

 Slowed cardiac conduction, tachycardia, ventricular fibrillation, heart block, and ventricular premature complexes (similar to Class Ia AA)  Sudden cardiac death (unclear association with QTc prolongation) – Avoid doses > 100mg / day amitriptyline equivalents

 Avoid in those with cardiovascular disease or established conduction abnormalities  Unclear increase in risk in those without pre-existing disease  Screen for known heart disease, syncope, palpitations, dyspnea, or chest pain  Baseline ECG recommended by some in those > 40 yrs of age (> 50 yrs of age based on APA Depression Guidelines  Routine ECG monitoring not recommended unless CV symptoms arise Ray WA, et al. Clin Pharmacol Ther 2004;75:234-241.

Gelenberg AJ, et al. Practice guideline for the treatment of patients with Major Depressive Disorder, 3rd Edition. www.psychiatryonline.org. Accessed June 26, 2012.

TCAs – Anticholinergic & Sedation  Muscurinic Ach receptor antagonists – Blurred vision, constipation, dry mouth, urine retention, constipation, tachycardia, confusion, delirium, increased ocular pressure – Secondary amines < tertiary amines

 Antihistaminergic effects (sedation, delirium) – Maprotiline, amitriptyline, doxepin, and trimipramine

TCAs – Behavioral Health Risks  Abrupt discontinuation – Withdrawal symptoms (GI, malaise, chills, rhinitis and myalgias) – Rebound depression  Increased suicidality vs. overdose toxicity – Boxed warning for children, adolescents, young adults (18-24 yrs of age) – Cardiac (QTc) and anticholinergic toxicity at doses as little as 10x prescribed  Risk of “switching” to mania but small Labbate, LA, Fava, M, Rosenbaum, JF, et al. Drugs for the treatment of depression. In: Handbook of Psychiatric Drug Therapy, 6th ed, Lippincott Williams & Wilkins, Philadelphia 2010.

Dallal A, et al. J Clin Psychopharmacology 1998;18:343-344.

Frye MA, et al. Am J Psychiatry 2009;166:164-172.

Van Scheyen JD, et al. Arch Gen Psychiatry 1979;36:560-565.

SSRI / SNRI Selective Serotonin Reuptake Inhibitors

Serotonin Norepinephrine Reuptake Inhibitors

Fluoxetine Sertraline Fluvoxamine Paroxetine* Citalopram* Escitalopram*

Venlafaxine Duloxetine Desvenlafaxine Milnacipran

*Small RCT data to support use in either chronic musculoskeletal or neuropathic pain

Table adapted from Lexi-Drugs Online. www.uptodate.com. Accessed June 26, 2012.

Serotonin Syndrome  Mental status changes

– Anxiety, agitated delirium, restlessness, disorientation

 Autonomic hyperactivity

– Diaphoresis, tachycardia, hyperthermia, HTN, vomiting, and diarrhea

 Neuromuscular changes

– Tremor, muscle rigidity, myoclonus, hyperreflexia, clonus

 Severity may range from benign to lethal  Solely a clinical diagnosis  Patient and caregiver education paramount  Consider serotonin active herbal / OTC products!!!

Boyer EW, et al. N Engl J Med 2005;352(11):1112-1120.

Mackay FJ, et al. Br J Gen Pract 1999;49(448)871-874.

Diagnosis of SS – Hunter Criteria  Serotonergic agent PLUS one of the following: – Spontaneous clonus – Inducible clonus and agitation or diaphoresis – Ocular clonus and agitation or diaphoresis – Tremor and hyperreflexia – Hypertonia – Temp above 38oC (100.4°F)

 Although clinical dx, consider CBC, BMP, INR, CPK, LFTs, UA, chest x-ray, head CT, to rule out differentials Dunkley EJ, et al. QJM 2003;96(9):635-642

SSRI / SNRI - Hyponatremia    

Incidence as high as 32% of those exposed Frequently seen within first 2 weeks of initiation SIADH-mediated Signs / symptoms – Fluid status related:

• History of fluid loss, decreased skin turgor, orthostatic or persistent hypotension

– CNS status related:

• Weakness, lethargy, headache, anorexia (these are also symptoms of worsening depression and common side effects of the drugs)

 Monitoring recommendations vary and are opinion-based

– Consider sodium monitoring within 1st month for those at risk

• Diuretics, female gender, older age, low BMI, CYP3A4 interactions, and mild hyperkalemia upon initiation

Jacob S, et al. Ann Pharmacother 2006;40(9):1618-1622.

Covyeou JA, et al. N Engl J Med 2007;356:94-95.

Movig KL, et al. Br J Clin Pharmacol 2002;53:363-369.

Appiani F. Psychiatry Weekly 2011;6(14):1.

SSRI / SNRI - Suicidality  Warnings  Effected populations  Timing of risk  Monitoring and followup

Morrato EH, et al. Am J Psychiatry 2008;165(1):42-50. http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/UCM096273. Accessed July 18, 2012.

SSRI / SNRI – Cardiac Conduction  Previously not associated with QTc prolongation or Torsades de

Pointes

 Citalopram > escitalopram  Dose limits – Citalopram 40mg adults, 20mg > 65 yrs – Escitalopram 20mg adults, 10mg > 65 yrs

 Consider baseline ECG in those with cardiac disease history Anon. Drug Safety Update 2011;5(5):A1. http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON137769. Accessed July 18, 2012. http://www.qtdrugs.org/. Accessed July 18, 2012.

SSRI / SNRI Bleeding Risk  Blocked serotonin uptake into platelet  De-amplification of platelet aggregation  Controversial data suggests: – Minimal risk of upper GI bleed as monotherapy – Increased risk of upper GI bleed in combination with NSAIDs – Acid suppression therapy decreases risk Dalton SO, et al. Arch Intern Med 2003;163(1):59-64.

Loke YK, et al. Aliment Pharmacol Ther 2008;27(1):31-40.

McCloskey DJ, et al. Transl Res 2008;151(3):168-172. de Abajo FJ, et al. Arch Gen Psychiatry 2008;65(7):795-803.

Anticonvulsants  Gabapentinoids (gabapentin, pregabalin)  Topiramate and zonisamide  Valproic acid / divalproex  Carbamazepine / oxcarbazepine

Anticonvulsants - Suicidality  Controversial  FDA analysis of data from 199 clinical trials of 11 anticonvulsants  Risk of suicidal thoughts or behaviors approximately doubles  May present as early as one week following initiation  Drug versus epilepsy? http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116847.htm. Accessed July 18, 2012.

Bell GS, et al. Epilepsia 2009;50(8)1933-1942.

Arana A, et al. N Engl J Med 2010;363(6):542-551.

Anticonvulsants - Dermatologic  Stevens-Johnson Syndrome (SJS) – Sloughing in < 10% of body surface area – Mucous membranes affected in > 90%

 Toxic epidermal necrolysis (TEN) – Sloughing in > 30% of body surface area – Mucous membranes almost always affected

 Drug rash with eosinophilia and systemic symptoms (DRESS) – Also called Drug induced hypersensitivity syndrome (DiHS) Bastuji-Garin S, et al. Arch Dermatol 1993;129(1):92-96.

Anticonvulsants - Dermatologic  90% of cases occur within first 60 days  Carbamazepine / oxcarbazepine? / phenytoin / zonisamide – HLA B*1502 monitoring recommended (Asian ancestry) – Do not rechallenge with aromatic anticonvulsants

 Lamotrigine – Higher risk in children – Assoc. with titration Chung WH, et al. Nature 2004;428(6982):486.

Yang CY, et al. Neurology 2011;77(23):2025-2033.

Mockenhaupt M, et al. Neurology 2005;64(7):1134-1138

CBZ

OXC

Anticonvulsants – Bone Disease  Enzyme inducing vs. non-enzyme inducing  Enzyme inducing – Increased catabolism of vitamin D and increased PTH

 Non-enzyme inducing – Intestinal calcium absorption inhibition (direct) – Osteoclastic bone resorption stimulation (direct)

Pack AM, et al. Ann Neurol 2005;57(2):252-257.

Ensrud KE, et al. Neurology 2004;62(11):2051-2057.

Kim SH, et al. Epilepsy Behav 2007;10(2):291-295.

Anticonvulsants – Bone Disease  Risk of fracture

– Epilepsy vs control (RR 2.2; 95% CI 1.9-2.50) – Anticonvulsant vs no anticonvulsant (RR 2.64; 95% CI 1.82-3.82)

 Does fracture risk increase in non-epileptic use of anticonvulsants?  General risk factors

– Female, post-menopausal, caucasion & asian, old age, tobacco use, low BMI, low Ca and vit D intake

 AED related risk factors

– High dose, multiple drug regimens, duration of therapy, chronic illnesses, metabolic acidosis, concomitant enzyme inducers

 Monitoring

– National Osteoporosis Foundation recommendations unclear – Some recommend BMD testing (> 5 yrs duration of enzyme inducers and valproate) – Routine calcium, phosphate, and 25-OHD levels

National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. http://www.nof.org. Accessed July 18, 2012.

Vestergaard P. Acta Neurol Scand 2005;112(5)277-286.

Espallargues M, et al. Osteoporosis Int 2001;12(10):811-822.

Cummings SR, et al. N Engl J Med 1995;332(12)767-773.

Anticonvulsants - Neurocognitive Psychomotor reaction time Learning, memory, and executive function Word finding Considerable variance based on: – Age – Multiple anticonvulsants – Serum drug concentrations  All anticonvulsants appear to have some effect on neuropsych batteries    

Meador KJ. Epilepsy Res 2006;68(1):63-67.

Pandina GJ, et al. Pediatr Neurol 2010;42(3):187-95.

Koch MW, Polman SKL. Oxcarbazepine versus carbamazepine monotherapy for partial onset seizures. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD006453. DOI: 10.1002/14651858.CD006453.pub2.

Hessen E, et al. Acta Neurol Scand 2009;119(3):194-198.

Skeletal Muscle Relaxants  Cyclobenzaprine – sedation, structurally a TCA  Tizanidine – sedating, hypotension, best data  Methocarbamol – less sedating, limiting evidence  Orphenadrine – sedating, sodium channel blockade  Carisoprodol – sedating, high abuse potential  Diazepam – sedating, high abuse potential  Metaxalone – less sedating, expensive  Baclofen – data primarily intrathecal  Dantrolene - hepatotoxicity

Case Vignette  45 year old female of asian descent presents for initial evaluation in your outpatient pain service. She has been well-controlled on the current regimen for > 5 years.  PMHx: chronic low back pain, osteoarthritis of the hips, fibromyalgia syndrome, anxiety, and depression  Meds: gabapentin, piroxicam, venlafaxine, and hydrocodone / acetaminophen (12 tabs / day)  SHx: + tob 1ppd, + EtOH 1 glass wine, - ilicit  FHx: Fa deceased STEMI age 45, Ma alive and well  What monitoring and patient education should be used?

Conclusions  Adjuvant and co-analgesics require judicious monitoring for safe use  Extensive patient education regarding potential adverse effects is paramount  Comorbid disease processes and concurrent medications may obscure adverse effects