Antidepressant and Anticonvulsant Adjuvant Therapy

Antidepressant and Anticonvulsant Adjuvant Therapy Deborah A. Ward, PharmD., BCOP, BCPS

Disclosure Information  Nothing to disclose

Learning Objectives  Identify the role of providing non-opioid treatment options in a variety of pain syndromes  Identify the drug therapy commonly prescribed  Outline monitoring parameters for the safe and effective use of adjuvant therapy with antidepressants and anticonvulsants

DEPRESSION AND PAIN

“The Interconnectedness of Body and Mind in Clinical Medicine� Bras et al

Chronic Pain A psychosomatic disorder with physical, mental, social, and spiritual components

Background • Patients with chronic pain frequently present with co-morbid psychiatric conditions – Depression – Anxiety – Personality disorders – Substance abuse/dependence disorders

• Research conducted in the 1980s demonstrated an increased prevalence of the above disorders in the chronic pain population versus the general public J of Beh Med Sept/Oct 2002;64(5): 773-786

Chronic Pain and Depression

CLBP Chronic upper extremity pain Entire US population

Current Risk of MDD 45% 80%

Lifetime Risk of MDD 65% 80%

5%

17%

MDD = Major Depressive Disorder

CLBP = Chronic Lower Back Pain

J of Beh Med Sept/Oct 2002;64(5): 773-786

Depression and Pain  Pain is a strong predictor of both onset and persistence of depression  Depression is a powerful predictor of pain  Greater impact than either disorder alone on functional status – Worsen disability – ↓active coping in patients suffering from pain – ↓ likelihood of favorable response of either condition to therapy – ↓ patient satisfaction with therapy Gen Hosp Psy 2009;31:206-219

Special Population - Pediatrics  8% of otherwise healthy children and adolescents experience severe chronic pain  Impact on normal daily life – Poor school attendance – Reduced participation in activities • Athletic and social

– Sleep disturbances

 Higher levels of distress, anxiety, and depression  Potential for all of the above to follow them into adulthood Pain Res Manage, Jan/Feb 2009;14(1):21-26

Suicide Risk - Pediatrics  In 2004, FDA issued advisory – Meta-analysis of all randomized studies of antidepressant use among children and adolescents – Twice the risk of suicidal thoughts and behaviors

 Black Box Warning – Applicable to all antidepressant agents regardless of class – An FDA-approved patient medication guide must be dispensed with the medication http://www.fda.gov/downloads/Drugs/DrugSafety/ucm089121.pdf

One Is Not Better Than The Other

Pediatrics 2010 May;125(5):876-888

Suicide Risk and Anticonvulsants  Wide range of indications and common use lead to safety concerns  2008 FDA mandated warning label changes for all anticonvulsants regarding increased risk of suicidal thoughts and behaviors – Meta-analysis including data from 199 placebo controlled trials of 11 anticonvulsants

 Risk increased within first 14 days of therapy JAMA 2010;303(14): 1401-1409

Suicide Risk - Elderly  Increase risk of suicidal behaviors – Suicide ideation, attempts, and death

 Enormous public health problem  Identified risk factors – Psychiatric illness, especially depression – Physical illness – Pain – Functional impairment – Social disconnectedness Curr Psy Rep 2011 June;13(3):234-241

Psychosocial Complexity of Pain

Curr Psy Rep 2011 June;13(3):234-241

Adjuvant Analgesic  Definition – Any drug with a primary indication other than pain, but with analgesic properties in some painful conditions

 Usually co-administered with analgesics – To enhance pain relief – Address pain that has not or sufficiently responded – Allow reduction of analgesic to reduce adverse effects

 Often first-line therapy in treatment of chronic nonmalignant pain

Major Classes of Adjuvant Analgesics  Antidepressants  Corticosteroids  Neuroleptics  α2-adrenergic agonists  Anticonvulsants  Local anesthetics  Bisphosphonates  Radiopharmaceuticals  Muscle relaxants The Oncologist 2004;9:571-591

How They Work

Amer Fam Physician Feb 2005;71(3):483-490

Where They Work

J of Pain Feb 2011;12(2):157-166

ANTIDEPRESSANT ADJUVANT PHARMACOTHERAPY

Efficacy of Antidepressants  Treat psychiatric co-morbid conditions  Inhibit ascending pain pathways  Inhibit prefrontal cortical areas responsible for “attention” to noxious stimuli  Exhibit direct effects on somatic symptoms CNS Spect March 2006;11(3):212-222

Indications Include…  Nerve injury  Diabetic neuropathy  Postherpetic neuralgia  Low back pathology  Fibromyalgia  Endometriosis  Arthritis  Neurological disorders – Multiple sclerosis – Parkinson disease

 Malignancy

Choosing an Agent  Goal – Antidepressant should have analgesic properties independent on its effect on mood • Provides pain relief in patients with or without depression

 Main pharmaceutical classes – Tricyclic antidepressants (TCAs) – Selective serotonin norepinephrine reuptake inhibitors (SNRIs) – Selective serotonin reuptake inhibitors (SSRIs) – Monoamine oxidase inhibitors (MAOIs) Bonica’s Management of Pain, 4th Edition

Tricyclic Antidepressants - TCAs  Considered first-line therapy  Most commonly used agents – Amitriptyline, nortriptyline, and desipramine

 Advantage – Decades of clinical experience – Low cost

 Disadvantage – Side effect profile

Tricyclic Antidepressants - TCAs  Dosing

– Once daily, usually at bedtime – Low initial dose with slow titration

• 25 mg most common starting dose ; 10 mg in frail and elderly • Increase every 3 – 5 days until diminution of pain complaints or max dose of 100 mg reached

 Maximal effect seen within several weeks  PK properties

– Well absorbed from the GI tract – Distributed to lungs, heart, brain, and liver – Steady state half life – wide interpatient variability – Pharmacologically active metabolites Bonica’s Management of Pain, 4th Edition

TCAs – Major Toxicities  Dose-dependent adverse effects – Sedation, Constipation, Dry mouth – Urinary retention – Orthostatic hypotension

 Relative contraindications – Benign prostate hyperplasia – Cardiac conduction defects • Including myocardial infarct and sudden death • Baseline EKG and evaluation of QTc interval

The SNRIs  MOA: block the reuptake of both serotonin (5HT) and norepinephrine (NE) with differing selectivity.

–Approximate potency ratios (5-HT:NE) • 1:1 Milnacipran • 1:10 Duloxetine • 1:30 Venlafaxine

 Less effective than TCAs but generally better tolerated CNS Spectrums Sept 2005;10(5):732-747

The SNRIs  Dosing – Slow dose titration at both initiation and discontinuation of therapy • If intolerable symptoms, resume previous dose and titrate even more gradually

 PK Properties – Oral absorption > 90% – Hepatic Metabolism via CYP1A2 and 2D6 to inactive metabolites – Widely variable distribution and elimination half-life

SSRI Efficacy

CNS Spect March 2006;11(3):212-222

ANTICONVULSANT ADJUVANT PHARMACOTHERAPY

Indications

Amer Fam Physician Feb 2005;71(3):483-490

First Generation Agents  Carbamazepine – Indicated for treatment of trigeminal neuralgia – Modest efficacy in diabetic neuropathy and postherpetic neuralgia

 Phenytoin  Use of both agents has significantly declined – Side effect profile: sedation, dizziness, nausea – Potential for drug-drug interactions

Gabapentin  First use of an anticonvulsant in neuropathic pain – Now used for both nonmalignant and cancer-related neuropathic pain

 Good tolerability  Lack of drug-drug interactions  First line therapy  Dosing – Start at 100 – 300 mg/day and increase every 3 days – Effective dosages range from 2400 – 3600 mg/day – Adequate trial of 1 – 2 weeks at MTD

Lamotrigine  Modest efficacy in trigeminal neuralgia  Inconsistent results in other neuropathies  Use limited by adverse reactions – Somnolence, dizziness, and ataxia – Potential for severe rash and SJS

Pregabalin  Analgesic effects due to binding to the α2-δ subunit of voltage-gated calcium channels on primary afferent neurons  Proven efficacy in PHN and PDN in multiple RTC  Effective daily dose 300 – 600 mg  Advantages over other therapies – Twice daily dosing – Can be rapidly titrated – Early onset of analgesic effect – Linear pharmacokinetics – No reported drug-drug interactions

Summary  Very few comparative trials for both the antidepressants and the anticonvulsants in the treatment of pain – Use is supported by partially controlled and uncontrolled trials, as well as clinical experience

 Initial drug selection – Comorbidities – Contraindications – Cost – Side effects

Regardless of what the clinical trials show…

If they are not tolerated – they are not efficacious