Antidepressant and Anticonvulsant Adjuvant Therapy

Deborah A. Ward, PharmD., BCOP, BCPS

Disclosure InformationNothing to disclose

Learning Objectives Identify the role of providing non-opioid treatment options in a

variety of pain syndromes Identify the drug therapy commonly prescribedOutline 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 PainA 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

Current Risk of MDD

Lifetime Riskof MDD

CLBP 45% 65%Chronic upper extremity

pain80% 80%

Entire US population 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

depressionDepression is a powerful predictor of painGreater 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 - Pediatrics8% 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

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

One Is Not Better Than The Other

Suicide Risk and AnticonvulsantsWide range of indications and common use lead to safety

concerns2008 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

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

Psychosocial Complexity of Pain

Adjuvant AnalgesicDefinition

–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 Neurolepticsα2-adrenergic agonists Anticonvulsants Local anesthetics Bisphosphonates RadiopharmaceuticalsMuscle 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 AgentGoal

–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 therapyMost 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 ToxicitiesDose-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 SNRIsMOA: 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 SNRIsDosing

–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

PhenytoinUse 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

LamotrigineModest efficacy in trigeminal neuralgia Inconsistent results in other neuropathiesUse 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