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* TricyclicSSRISNRI 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 inhibitor

Review of Antidepressant Analgesia for Older Agents Meta-analysis by Onghena (1992)Synthesis by Magni (1991) DiagnosisNo. of StudiesEffect Size Diabetic neuropathy11.71Responsive Postherpetic neuralgia21.44Responsive Tension headache61.11Responsive Migraine40.82Responsive Atypical facial pain30.81Responsive Chronic back pain50.64Minimal clinical benefit Rheumatological pain100.37Fibrositis responsive; Osteo- and rheumatoid arthritis probably responsive Not specified or mixed70.23Probable 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 – gabapentin – pregabalin Diabetic neuropathy – carbamazepine – phenytoin – gabapentin – Lamotrigine – pregabalin HIV-associated neuropathy – lamotrigine Trigeminal neuralgia – carbamazepine – lamotrigine – oxcarbazepine Fibromyalgia - pregabalin Central poststroke pain – lamotrigine

Screening Week Mean pain score † P<0.01; ‡ P<0.05. Gabapentin in the Treatment of Painful Diabetic Neuropathy* *Not approved by FDA for this use. Placebo Gabapentin Adapted from Backonja M et al. JAMA. 1998;280: N= † † ‡ † ‡‡ ‡

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 Alpha- Adrenergic 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 Nerve Injury Hyperalgesia Mu-Opioid-R Activation Mu-Opioid Tolerance NMDA-R Neurotoxicity PKC  Excitability  Mu-Efficacy Inhibitors

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- Cardiac dysrhythmias – Anticholinergic 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: 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.