Nonopioid Analgesics Antidepressants, Adjuvant Therapies, and Muscle Relaxants. Abigail Brooks, PharmD, BCPS Developed by: Chris Herndon, PharmD, CPE

Transcription

1 Nonopioid Analgesics Antidepressants, Adjuvant Therapies, and Muscle Relaxants Abigail Brooks, PharmD, BCPS Developed by: Chris Herndon, PharmD, CPE

2 Disclosures Nothing to disclose

3 Learning Objectives Describe where adjuvant analgesics act in the pain pathways State which adjuvants are considered first-line analgesics Choose an adjuvant analgesic for a given patient, based on current guidelines and /or evidence-based medicine Compare risks and benefits of different adjuvant analgesics for a given patient

4 Pharmacotherapy (based on a new taxonomy) Drug Class / Mechanism of action Opioids Anticonvulsants TCAs SNRIs Local anesthetics NSAIDs Acetaminophen NMDA antagonists Capsaicin Cannabinoids Corticosteroids Skeletal muscle relaxants IASP Pharmacology of Pain Antinociceptive Peripheral desensitization Descending modulator Descending modulator Peripheral desensitization Antinociceptive Antinociceptive Antihyperalgesic Peripheral desensitization Antinociceptive Peripheral desensitization Descending modulator Beaulieu P, Lussier D, Porreca F, Dickenson AH, eds. Pharmacology of pain. Seattle, WA: International Association for the Study of Pain (IASP) Press; 2010.

5 Where Do Adjuvants Work?

6 Adjuvants and Co-Analgesics Acetaminophen NSAIDs Antidepressants Anticonvulsants Anesthetics Skeletal muscle relaxants Antipsychotics Other Antidepressants Anticonvulsants Anesthetics Skeletal muscle relaxants

7 Anticonvulsants (available in US, excluding benzodiazepines) 1 st Generation Anticonvulsants 2 nd / 3 rd Generation Anticonvulsants Carbamazepine (Tegretol, others) Ethosuximide (Zarontin) Phenobarbital Phenytoin / Fosphenytoin (Dilantin) Primidone (Mysoline) Valproic Acid (Depakote, others) Eslicarbazepine (Aptiom) Ezogabine (Potiga) Felbamate (Felbatol) Gabapentin (Neurontin) Lacosamide (Vimpat) Lamotrigine (Lamictal) Levetiracetam (Keppra) Oxcarbazepine (Trileptal, others) Perampanel (Fycompa) Pregabalin (Lyrica) Rufinamide (Banzel) Tiagabine (Gabitril) Topiramate (Topamax, others) Vigabatrin (Sabril) Zonisamide (Zonegran)

8 Mechanism of Action 1 st Generation Anticonvulsants VSSC K GluR-I GABA Ca CA-I Carbamazepine x Ethosuximide x Phenobarbital x (A) Phenytoin / Fosphenytoin x Primidone x x Valproic Acid / Divalproex x x (B) x

9 Mechanism of Action 2nd / 3rd Generation Anticonvulsants

10 Utility in Pain 1st Generation Anticonvulsants Results compiled from Medline and ClinicalTrials.gov (queried July 9, 2014) Animal data may include models of hyperalgesia, musculoskeletal, or neuropathy Level IV/V data = case reports or series Level III = quasi experimental studies Level II = randomized controlled trials

11 Utility in Pain 2nd / 3rd Generation Anticonvulsants

12 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 1 week following initiation Drug vs epilepsy? Accessed July 18, Bell GS, et al. Epilepsia. 2009;50(8) Arana A, et al. N Engl J Med. 2010;363(6):

13 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.

14 Anticonvulsants Dermatologic (cont d) 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): Mockenhaupt M, et al. Neurology. 2005;64(7): CBZ OXC

15 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): Ensrud KE, et al. Neurology. 2004;62(11): Kim SH, et al. Epilepsy Behav. 2007;10(2):

16 Anticonvulsants Bone Disease (cont d) Risk of fracture Epilepsy vs control (RR 2.2; 95% CI ) Anticonvulsant vs no anticonvulsant (RR 2.64; 95% CI ) Does fracture risk increase in non-epileptic use of anticonvulsants? General risk factors Female, post-menopausal, Caucasian & 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 years 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. Accessed July 18, Vestergaard P. Acta Neurol Scand. 2005;112(5) Espallargues M, et al. Osteoporosis Int. 2001;12(10): Cummings SR, et al. N Engl J Med. 1995;332(12):

17 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): Pandina GJ, et al. Pediatr Neurol. 2010;42(3): Koch MW, Polman SKL. Oxcarbazepine versus carbamazepine monotherapy for partial onset seizures. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD DOI: / CD pub2. Hessen E, et al. Acta Neurol Scand. 2009;119(3):

18 Lidocaine Topical anesthetic and Class 1b anti-arrhythmic Sodium channel blockade Na(v) 1.7 Inhibition of acid sensing ion channels (ASIC) Available via OTC (0.5-4%) and prescription (5%) Lidocaine 5% patch applied directly to area of PHN No more than 3 patches concurrently 12 hours on, 12 hours off Infusion targeted to 5 mg/l Lin J, et al. Inhibition of acid sensing ion channel currents by lidocaine in cultured mouse corticol neurons. Anesth Analg 2011:112: Kaliq W, et al. Topical lidocaine for the treatment of postherpetic neuralgia. Cochrane Database Syst Rev 2007;18:CD Schwartzman RJ, et al. Pain Med 2009;10:

19 Antidepressants SNRI Venlafaxine (Effexor) Desvenlafaxine (Pristiq) Duloxetine (Cymbalta) Milnacipran (Savella) Levomilnacipran (Fetzima) Atypicals Bupropion (Wellbutrin, others) Mirtazapine (Remeron) Trazodone (Desryel Vilazodone (Viibryd) TCA (tertiary vs secondary) Doxepin Imipramine Amitriptyline Clomipramine Protriptyline Nortriptyline Desipramine SSRIs? Paroxetine (Paxil) Escitalopram (Lexapro) In order of H1-Ki

20 Tricyclic Antidepressants (TCAs) Tertiary amines Secondary amines (NE>5HT) Amitriptyline Imipramine Clomipramine Doxepin Trimipramine 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: McQuay. Pain. 1996;68: Table adapted from Lexi-Drugs Online. Accessed June 26, 2012.

21 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 > 100 mg / 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 years of age (> 50 years 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: Gelenberg AJ, et al. Practice guideline for the treatment of patients with Major Depressive Disorder, 3 rd Edition. Accessed June 26, 2012.

22 TCAs Anticholinergic & Sedation Muscarinic 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

23 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 years 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 Dallal A, et al. J Clin Psychopharmacology. 1998;18: Frye MA, et al. Am J Psychiatry. 2009;166: Van Scheyen JD, et al. Arch Gen Psychiatry. 1979;36:

24 SSRI / SNRI / Atypical Selective Serotonin Reuptake Inhibitors Fluoxetine Sertraline Fluvoxamine Paroxetine* Citalopram* Escitalopram* Serotonin Norepinephrine Reuptake Inhibitors Venlafaxine Duloxetine Desvenlafaxine Milnacipran Levomilnacipran Atypical Bupropion Mirtazapine Trazodone Vilazodone *Small RCT data to support use in either chronic musculoskeletal or neuropathic pain Table adapted from Lexi-Drugs Online. Accessed June 26, 2012.

25 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, and 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): Mackay FJ, et al. Br J Gen Pract. 1999;49(448):

26 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 38 o C (100.4 o 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):

27 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): Covyeou JA, et al. N Engl J Med 2007;356: Movig KL, et al. Br J Clin Pharmacol 2002;53: Appiani F. Psychiatry Weekly 2011;6(14):1.

28 SSRI / SNRI Suicidality Warnings Effected populations Timing of risk Monitoring and followup Morrato EH, et al. Am J Psychiatry. 2008;165(1): Accessed July 18, 2012.

29 SSRI / SNRI Cardiac Conduction Previously not associated with QTc prolongation or Torsades de Pointes Citalopram > escitalopram Dose limits Citalopram 40 mg adults, 20 mg 65 years Escitalopram 20 mg adults, 10 mg 65 years Consider baseline ECG in those with cardiac disease history Anon. Drug Safety Update. 2011;5(5):A1. Accessed July 18, Accessed July 18, 2012.

30 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): Loke YK, et al. Aliment Pharmacol Ther. 2008;27(1): McCloskey DJ, et al. Transl Res. 2008;151(3): de Abajo FJ, et al. Arch Gen Psychiatry. 2008;65(7):

31 Muscle Relaxants Antispasmodics Cyclobenzaprine Metaxalone Methocarbamol Orphenadrine citrate Carisoprodol Antispasticity agents Tizanidine Baclofen Diazepam Dantrolene All equally effective for short-term relief of low back pain Not more effective than NSAIDs for acute low back pain Not recommended for chronic pain Chou R, et al. J Pain Symptom Manage. 2004;28: Van Tulder MW, et al. Cochrane Database Syst Rev. 2003;(2):CD

32 III. Centrally acting agents (spasmolytic drugs) Muscle Relaxants (cont d) Mechanism The stretch reflex: 1. muscle spindle 2. Ia afferents 3. efferents (motor neurons) 4. contraction CNS-acting drugs inhibit stretch reflex Descending inhibitory neurons (not shown): 1. Inhibit alpha motor neurons CNS-acting drugs activate descending inhibitory pathways From Basic and Clinical Pharmacology, 11 th edition

33 III. Centrally acting agents (spasmolytic drugs) Muscle Relaxants (cont d) Baclofen GABA analogue Selective GABA-B receptor agonist ( K+ conductance, Ca++ conductance ) Muscle relaxant and analgesic (reduced substance P) Adverse effects: somnolence, increased seizure activity Tizanidine Agonist of α2 receptors (presynaptic) Reduces adrenergic input to alpha motor neurons No effect on spinal cord reflex Less antihypertensive effect than clonidine Side effects: hypotension, asthenia BA-B receptor and effects: Principles of Pharmacology, 2nd edition

34 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

35 NMDA Receptor Antagonists Dextromethorphan Ketamine Methadone Memantine Amantadine Felbamate Levorphanol Ca Ca Ca Mg Ca Post-synaptic bouton

36 NMDA Receptor Antagonists (cont d) Mostly used for possible opioid-sparing effects Ketamine useful for acute post-op pain Several studies for chronic pain, very few positive results for ketamine Adverse effects are dose-limiting Potential for abuse

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