Non-Opioid
Pharmacotherapeutic Options
in Pain Management
Charles E. Argoff, M.D.
Professor of Neurology
Albany Medical College
Director, Comprehensive Pain Program
Albany Medical Center
“Discouraging data on the antidepressant.”
Multidisciplinary Treatment of
Chronic Pain

Pharmacotherapy and other
medical/surgical care with appropriate
medicine reorganization
 Restorative care including active physical
and occupational therapy
 Psychological counseling utilizing
cognitive-behavioral pain management
strategies
Aim for Monotherapy
Titrate only one drug at a time
Pharmacotherapy
Guidelines
1.
Medication must result in:
–
–
Significant pain relief
Tolerable side effects
function
Pharmacotherapy
Guidelines
2.
Both physician & patient must realize
significant individual variability
Pharmacotherapy
Guidelines
3.
Slow titration until either:
a) Significant pain relief
b) Intolerable side effects
c) “Toxic serum level”
Pharmacotherapy
Guidelines
4.
Educate the patient
Non-Opiate Pharmacotherapy

NSAIDs/Cox-2
 Acetaminophen
 Antidepressants
 Anticonvulsants
 Oral local anesthetics
 Alpha adrenergic agents
 Neuroleptics
 NMDA receptor antagonists
 Muscle relaxants
 Topical analgesics
 Emerging Agents
Non-Opiate Pharmacotherapy


NSAIDs/Cox-2
Acetaminophen
 Antidepressants
 Anticonvulsants
 Oral local anesthetics
 Alpha adrenergic agents
 Neuroleptics
 NMDA receptor antagonists
 Muscle relaxants
 Topical analgesics
 Emerging Agents
Non-Opiate Pharmacotherapy

NSAIDs/Cox-2

Acetaminophen

Antidepressants
 Anticonvulsants
 Oral local anesthetics
 Alpha adrenergic agents
 Neuroleptics
 NMDA receptor antagonists
 Muscle relaxants
 Topical analgesics
 Emerging Agents
Non-Opiate Pharmacotherapy


NSAIDs/Cox-2
Acetaminophen

Antidepressants

Anticonvulsants
 Oral local anesthetics
 Alpha adrenergic agents
 Neuroleptics
 NMDA receptor antagonists
 Muscle relaxants
 Topical analgesics
 Emerging Agents
Antidepressants*
Tricyclic
SSRI
SNRI
Amitriptyline
(Elavil®)
Fluoxetine (Prozac®)
Duloxetine#
(Cymbalta)
Desipramine
(Norpramin®)
Paroxetine (Paxil®)
Venlafaxine
(Effexor®)
Doxepin (Sinequan®)
Sertraline (Zoloft®)
Minalcipran#
(Savella)
Imipramine
(Tofranil®)
Fluvoxamine
(Luvox®)
Desvenlafaxine
(Pristiq)
Nortriptyline
(Pamelor®)
Citalopram
(Celexa)
* = Partial list # = FDA approved for at least one pain disorder
SSRI = selective serotonin reuptake inhibitor SNRI = serotonin norepinephrine reuptake
Review of Antidepressant
Analgesia for Older Agents
Meta-analysis by Onghena (1992)
Diagnosis
Synthesis by Magni (1991)
No. of Studies
Effect Size
Diabetic neuropathy
1
1.71
Responsive
Postherpetic neuralgia
2
1.44
Responsive
Tension headache
6
1.11
Responsive
Migraine
4
0.82
Responsive
Atypical facial pain
3
0.81
Responsive
Chronic back pain
5
0.64
Minimal clinical benefit
Rheumatological pain
10
0.37
Fibrositis responsive;
Osteo- and rheumatoid
arthritis probably
responsive
Not specified or mixed
7
0.23
Probable effect
Non-Opiate Pharmacotherapy

NSAIDs/Cox-2
 Acetaminophen
 Antidepressants
 Anticonvulsants
 Oral local anesthetics
 Alpha adrenergic agents
 Neuroleptics
 NMDA receptor antagonists
 Muscle relaxants
 Topical analgesics
 Emerging Agents
Anticonvulsants






Carbamazepine*
Divalproex sodium*
Gabapentin*
Pregabalin*
Clonazepam
Phenytoin






*Has FDA indication for pain/headache
Lamotrigine
Topiramate*
Zonisamide
Oxcarbazepine
Levatriacetam
Lacosamide
Clinical Syndromes and
Anticonvulsant Use

Postherpetic neuralgia

– lamotrigine
– gabapentin
– pregabalin


– carbamazepine
– gabapentin
– Lamotrigine
– pregabalin
Trigeminal neuralgia
– carbamazepine
– lamotrigine
– oxcarbazepine
Diabetic neuropathy
– phenytoin
HIV-associated neuropathy

Fibromyalgia
- pregabalin
 Central poststroke pain
– lamotrigine
Mean pain score
Gabapentin in the Treatment
of Painful Diabetic
10
Placebo
Neuropathy*
Gabapentin
8
N=165
6
4
†
†
2
‡
†
†
‡
‡
‡
6
7
8
P<0.01; ‡P<0.05.
0
Screening
1
2
3
4
5
Week
*Not approved by FDA for this use.
46
Adapted from Backonja M et al. JAMA. 1998;280:1831-1836.
Non-Opiate Pharmacotherapy

NSAIDs/Cox-2
 Acetaminophen
 Antidepressants
 Anticonvulsants
 Oral local anesthetics
 Alpha adrenergic agents
 Neuroleptics
 NMDA receptor antagonists
 Muscle relaxants
 Topical analgesics
 Emerging Agents
Non-Opiate Pharmacotherapy

NSAIDs/Cox-2
 Acetaminophen
 Antidepressants
 Anticonvulsants
 Oral local anesthetics
 Alpha adrenergic agents
 Neuroleptics
 NMDA receptor antagonists
 Muscle relaxants
 Topical analgesics
 Emerging Agents
Currently Available AlphaAdrenergic Agonists

Clonidine
 Tizanidine
Possible Effective Uses of Tizanidine







Trigeminal neuralgia (Fromm 1993)
Chronic low back pain(Berry 1988)
Cluster headache (D’alessandro 1996)
Chronic tension-type headache (Nakashima 1994)
Spasmodic torticollis (Houten 1984)
Neuropathic pain
Chronic headache(2002)
Non-Opiate Pharmacotherapy

NSAIDs/Cox-2
 Acetaminophen
 Antidepressants
 Anticonvulsants
 Oral local anesthetics
 Alpha adrenergic agents
 Neuroleptics
 NMDA receptor antagonists
 Muscle relaxants
 Topical analgesics
 Emerging Agents
Non-Opiate Pharmacotherapy

NSAIDs/Cox-2
 Acetaminophen
 Antidepressants
 Anticonvulsants
 Oral local anesthetics
 Alpha adrenergic agents
 Neuroleptics
 NMDA receptor antagonists
 Muscle relaxants
 Topical analgesics
 Emerging Agents
NMDA receptor antagonists
Preclinical Data
Mu-Opioid-R
Activation
Nerve Injury
NMDA-R
Inhibitors
PKC
 Excitability
Neurotoxicity
Hyperalgesia
 Mu-Efficacy
Mu-Opioid
Tolerance
Drugs with Potential NMDA-R
Antagonist Properties

Dextromethorphan
 Ketamine
 d-Methadone
 Amantadine
 Memantine
 Amitriptyline
DEXTROMETHORPHAN
Postherpetic Neuralgia &
Painful diabetic neuropathy

2 RCTs Crossover: 6 weeks
– Dextromethorphan alone vs placebo

DN:
– mean daily dose = 381 mg/day
– Pain decreased ( p=0.01)

PHN:
– mean daily dose = 439 mg/day
– Did not significantly reduce pain
(Nelson 1997)
Non-Opiate Pharmacotherapy

NSAIDs/Cox-2
 Acetaminophen
 Antidepressants
 Anticonvulsants
 Oral local anesthetics
 Alpha adrenergic agents
 Neuroleptics
 NMDA receptor antagonists
 Muscle relaxants
 Topical analgesics
 Emerging Agents
Muscle Relaxants

Cyclobenzaprine (Flexeril®)
 Carisoprodol (Soma®)
 Methocarbamol (Robaxin®)
 Metaxalone (Skelaxin®)
 Orphenadrine citrate (Norflex®)
Cyclobenzaprine

Structurally similar to tricyclics
 Centrally acting
 Nocturnal muscle spasm effects
 Side effects:
– Drowsiness
– Anticholinergic





- Cardiac dysrhythmias
Dry mouth
Blurred vision
Urine retention
Constipation
Increased intraocular pressure
Carisoprodol

Precursor of meprobamate
 Centrally active
 Reduction of muscle spasm
 Side effects:
– Sedation, drowsiness, dependence
– Withdrawal symptoms





Agitation
Anorexia
N/V
Hallucination
Seizures
Methocarbamol

Investigative usage: MS
 Daily dosage: 1000 mg qid
 Side effect: drowsiness
 Mechanism of action:
– Centrally active
– Inhibits polysynaptic reflexes

Clinical effects:
– Reduction of muscle spasms
Metaxalone

Daily dosage: 400-800 mg tid
 Clinical effects:
– Reduction in muscle spasm

Side effects:
– Nausea
– Drowsiness
– Dizziness
Orphenadrine Citrate

Investigative usage: SCI
 Daily dosage: 100 mg bid
 Analog of diphenhydramine
 Given IV for antispasticity trials
 Side effects:
– Anticholinergic
– Rare aplastic anemia
Non-Opiate Pharmacotherapy

NSAIDs/Cox-2
 Acetaminophen
 Antidepressants
 Anticonvulsants
 Oral local anesthetics
 Alpha adrenergic agents
 Neuroleptics
 NMDA receptor antagonists
 Muscle relaxants
 Topical analgesics
 Emerging Agents
Topical Analgesics: Key
Facts

Topical agents are active within the skin, soft
tissues and peripheral nerves.
 In contrast to transdermal, oral or parenteral
medications, use of a topical agent does not result
in clinically significant serum drug levels.
 Other benefits include lack of systemic side
effects and drug-drug interactions.
 The mechanism of action of a topical analgesic is
unique to the specific agent considered.
Topical Treatments for
Chronic Pain







Diclofenac (patch/gel/lotion)
Aspirin
Capsaicin
Local anesthetics
- lidocaine patch 5%/eutectic mixture of local anesthetics
Tricyclic antidepressants
Opiates
Investigational agents
Non-Opiate Pharmacotherapy

NSAIDs/Cox-2
 Acetaminophen
 Antidepressants
 Anticonvulsants
 Oral local anesthetics
 Alpha adrenergic agents
 Neuroleptics
 NMDA receptor antagonists
 Muscle relaxants
 Topical analgesics
 Emerging Agents
Emerging Analgesics

Botulinum Toxin (Type A, Type B)
 New intraspinal agents
 New topical agents
 Cannabinoids
 Bisphosphonates
Summary

Numerous pharmacotherapeutic options are
available for the management of chronic pain.
 Proper evaluation including pain assessment is key
to providing the best analgesic approach.
 Optimizing analgesia in the long term care setting
requires achieving a proper balance among
efficacy, adverse effects, cost and other factors.