Non-Opioid Pharmacotherapeutic Options in Pain Management

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

PharmacotherapyGuidelines • Medication must result in: • Significant pain relief • Tolerable side effects function

Pharmacotherapy Guidelines • Both physician & patient must realize significant individual variability

Pharmacotherapy Guidelines • Slow titration until either: • Significant pain relief • Intolerable side effects • “Toxic serum level”

Pharmacotherapy Guidelines • 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

Antidepressants*

Review of Antidepressant Analgesia for Older Agents

Carbamazepine* Divalproex sodium* Gabapentin* Pregabalin* Clonazepam Phenytoin *Has FDA indication for pain/headache Lamotrigine Topiramate* Zonisamide Oxcarbazepine Levatriacetam Lacosamide Anticonvulsants

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 Clinical Syndromes and Anticonvulsant Use

Gabapentin in the Treatment of Painful Diabetic Neuropathy* 10 Placebo Gabapentin 8 N=165 6 Mean pain score 4 † † ‡ † ‡ ‡ ‡ 2 †P<0.01; ‡P<0.05. 0 Screening 1 2 3 4 5 6 7 8 Week *Not approved by FDA for this use. Adapted from Backonja M et al. JAMA. 1998;280:1831-1836. 46

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)

Nerve Injury Mu-Opioid-RActivation NMDA-R PKC Inhibitors  Excitability Neurotoxicity  Mu-Efficacy Hyperalgesia Mu-Opioid Tolerance NMDA receptor antagonistsPreclinical Data

Drugs with Potential NMDA-R Antagonist Properties • Dextromethorphan • Ketamine • d-Methadone • Amantadine • Memantine • Amitriptyline

DEXTROMETHORPHANPostherpetic 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)

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: 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

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

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.

Non-Opioid Pharmacotherapeutic Options in Pain Management