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