Pharmacotherapeutic Options in Pain Management

Pharmacotherapeutic Options in Pain Management Charles E. Argoff, M.D. Director, Cohn Pain Management Center North Shore University Hospital Assistant Professor of Neurology New York University School of Medicine Acute vs Chronic Pain Characteristic Cause Acute Pain Generally known Chronic Pain Often unknown Duration of pain Short, well-characterized Underlying disease Persists after healing, 3 mo Underlying disease and pain disorder Treatment approach Nociceptive vs Neuropathic Pain Nociceptive Pain Caused by activity in neural pathways in response to potentially tissue-damaging stimuli Mixed Type Caused by a combination of both primary injury or secondary effects Neuropathic Pain Initiated or caused by primary lesion or dysfunction in the nervous system CRPS* Postoperative pain Mechanical low back pain Arthritis Sickle cell crisis Postherpetic neuralgia Trigeminal neuralgia Neuropathic low back pain Sports/exercise injuries *Complex regional pain syndrome Distal polyneuropathy (eg, diabetic, HIV) Central poststroke pain Potential Descriptions of Chronic Pain  Sensations – burning – paresthesia – paroxysmal – lancinating – electriclike – raw skin – shooting – deep, dull, bonelike  Cardinal signs/symptoms – allodynia: pain from a stimulus that does not normally evoke pain   thermal mechanical – hyperalgesia: exaggerated response to a normally painful stimulus ache Pathophysiology of Chronic Pain          Chemical excitation of nonnociceptors Recruitment of nerves outside of site of injury Excitotoxicity Sodium channels Ectopic discharge Deafferentation Central sensitization – maintained by peripheral input Sympathetic involvement Antidromic neurogenic inflammation Pathophysiology: Peripheral Sensitization Nociceptor Nociceptor Innocuous stimulus Na+ channels Pain sensation Adapted from Woolf CJ et al. Lancet. 1999;353:1959-1964. Pathophysiology: CentralNormal sensory Sensitization function Ab fiber mechanoreceptor Innocuous Na+ stimulus channel Na+ channel Weak synapse Nonpainful sensation Increased nociceptor drive leads to central sensitization of dorsal horn neurons Innocuous Na+ stimulus channel Na+ channel Increased synapsis strength Painful sensation Adapted from Woolf CJ et al. Lancet. 1999;353:1959-1964. Pathophysiology: Peripheral and Central Sensitization “Discouraging data on the antidepressant.” Assessment of Pain Intensity Verbal Pain Intensity Scale No pain Mild Moderate Severe Very Worst pain pain pain severe possible pain pain Visual Analog Scale Worst possible pain No pain 0–10 Numeric Pain Intensity Scale Faces Scale 0 No pain 1 2 3 4 5 6 7 8 9 10 Moderate pain Worst possible pain 0 1 2 3 4 5 Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice. FA Davis; 1996:8-10. Wong DL. Waley and Wong’s Essentials of Pediatric Nursing. 5th ed. Mosby, Inc.; 1997:1215-1216. 21 McCaffery M, Pasero C. Pain: Clinical Manual. Mosby, Inc. 1999:16. Assessment of Pain Intensity Verbal Pain Intensity Scale No pain Mild Moderate Severe Very Worst pain pain pain severe possible pain pain Visual Analog Scale Worst possible pain No pain 0–10 Numeric Pain Intensity Scale Faces Scale 0 No pain 1 2 3 4 5 6 7 8 9 10 Moderate pain Worst possible pain 0 1 2 3 4 5 Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice. FA Davis; 1996:8-10. Wong DL. Waley and Wong’s Essentials of Pediatric Nursing. 5th ed. Mosby, Inc.; 1997:1215-1216. 21 McCaffery M, Pasero C. Pain: Clinical Manual. Mosby, Inc. 1999:16. 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 Antidepressants* Tricyclic Amitriptyline (Elavil®) Desipramine (Norpramin®) Doxepin (Sinequan®) Imipramine (Tofranil®) Nortriptyline (Pamelor®) SSRI Fluoxetine (Prozac®) Paroxetine (Paxil®) Sertraline (Zoloft®) Fluvoxamine (Luvox®) Citalopram (Celexa) Other Nefazodone (Serzone®) Venlafaxine (Effexor®) Trazodone (Desyrel®) Bupropion (Wellbutrin®) *Partial list SSRI = selective serotonin reuptake inhibitor Review of Antidepressant Analgesia Meta-analysis by Onghena (1992) Diagnosis Diabetic neuropathy Postherpetic neuralgia Tension headache Migraine Atypical facial pain Chronic back pain Rheumatological pain No. of Studies 1 2 6 4 3 5 10 Synthesis by Magni (1991) Effect Size 1.71 1.44 1.11 0.82 0.81 0.64 0.37 Responsive Responsive Responsive Responsive Responsive Minimal clinical benefit Fibrositis responsive; Osteo- and rheumatoid arthritis probably responsive Probable effect Not specified or mixed 7 0.23 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 Anticonvulsants      Carbamazepine* Divalproex sodium* Gabapentin Clonazepam Phenytoin       Lamotrigine Topiramate Zonisamide Oxcarbazepine Levatriacetam Tiagabine *Has FDA indication for pain/headache Anticonvulsant Drugs and Neuropathic Pain Disorders*   Postherpetic neuralgia – gabapentin   HIV-associated neuropathy – lamotrigine Diabetic neuropathy – carbamazepine Trigeminal neuralgia – carbamazepine – lamotrigine – oxcarbazepine – phenytoin – gabapentin – lamotrigine  Central poststroke pain – lamotrigine *Not approved by FDA for this use. 43 Gabapentin in the Treatment of Painful Diabetic 10 Placebo Neuropathy* Gabapentin Mean pain score 8 6 4 † N=165 † ‡ † † ‡ ‡ ‡ 2 0 Screening 1 2 3 P<0.01; ‡P<0.05. 4 Week 5 6 7 8 *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) Efficacy of Tizanidine in Neuropathic Pain: An Open-Label Study  Trial Design:  Marilyn R. Semenchuk, PharmD, BCPP; Scott Sherman, MD University of Arizona, Neurology Clinic – Open-label (N=22) 14 peripheral neuropathy, 1 diabetic neuropathy, 3 reflex sympathetic dystrophy, 1 radiculopathy, 2 nerve damage, 1 trigeminal neuralgia – 8 week treatment duration – Zanaflex initiated at dose of 4 mg qd hs for 7 days and increased by 2 mg – 8 mg weekly and taken in divided doses up to three time a day – The dose was escalated to the patient’s effective or maximum tolerated dose or a maximum of 36 mg/day Efficacy of Tizanidine in Neuropathic Pain: An Open-Label Study  Outcome Measures: Marilyn R. Semenchuk, PharmD, BCPP; Scott Sherman, MD University of Arizona, Neurology Clinic – Mean average weekly pain rating from patient diary (VAS) – Biweekly patient global assessment of pain relief – Mean biweekly scores of Neuropathic Pain Scale – Mean biweekly scores on the Wisconsin Brief Pain Inventory Efficacy of Tizanidine in Neuropathic Pain: An Open-Label Study  Results: Marilyn R. Semenchuk, PharmD, BCPP; Scott Sherman, MD University of Arizona, Neurology Clinic – Zanaflex may be an effective treatment of neuropathic pain in many patients and is generally well tolerated, offering an alternative for patients unable to tolerate other medication – The mean effective or maximum tolerated dose was 23 mg/day, the median dose was 24 mg/day and the dose range was 6 – 36 mg/day – Inhibition of the synaptic transmission of nociceptive stimuli in the spinal pathways may mediate this effect Efficacy of Tizanidine in Neuropathic Pain: An Open-Label Study Marilyn R. Semenchuk, PharmD, BCPP; Scott Sherman, MD University of Arizona, Neurology Clinic 23% 68% 9% Pain Improved/Pain Free Pain Worse Pain Unchanged 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 Advances in Opioid Analgesia Nerve Injury NMDA-R Inhibitors PKC Mu-Opioid-R Activation  Excitability Hyperalgesia Neurotoxicity  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       Aspirin preparations – eg, aspirin in chloroform or ethyl ether Capsaicin Local anesthetics - lidocaine patch 5%/eutectic mixture of local anesthetics Tricyclic antidepressants Opiates Investigational agents Capsaicin  Neuropathic pain states studied include: diabetic neuropathy, PHN, post-mastectomy pain, HIV neuropathy.  Non-neuropathic pain states such as osteoarthritis have been studied as well.  Efficacy demonstrated in some of these studies but limited by adverse effects and compliance issues.  New formulations are being studied. Topical Lidocaine Patch 5%  Lidocaine 5% in pliable patch  Up to 3 patches applied once daily directly over painful site – 12 h on, 12 h off (FDA-approved label) – recently published data indicate 4 patches(18–24h) safe  Efficacy demonstrated in 3 randomized controlled trials in postherpetic neuralgia  Systemic side effects unlikely – most common side effect: application-site sensitivity  Clinically insignificant serum lidocaine levels  Mechanical barrier may decrease allodynia EMLA®  EMLA®: not FDA approved for any specific neuropathic pain state  One controlled study of use of EMLA® in the treatment of PHN demonstrated equal efficacy with placebo  Several uncontrolled studies have supported the use of EMLA® in PHN Topical Local Anesthetics for NonNeuropathic Pain States  Low back pain  Osteoarthritis  Chronic myofascial pain  Acute soft tissue injury pain  Post-operative pain Topical Opiates  1. Galeotti N, DeCesare Mannelli L, Mazzanti G, et al. Menthol: a natural analgesic compound. Neurosci Lett 2002 Apr 12;322(3):145-148. This article is particularly interesting as the authors review evidence which suggests that one of the mechanisms of analgesia for menthol, a common ingredient in over the counter preparations may actually be the activation of kappa opiate receptors. Topical Morphine Treatment in Cancer-Related Pain  Effect of topical morphine for mucositisassociated pain following concomitant chemoradiotherapy for head and neck carcinoma. (Cerchietti LC, Navigante AH, Bonomi MR, et al., Cancer 2002 Nov 15;95(10): 2230-6.) Patients (n=26) with cancer-related mucositis treated with topical morphine or topical lidocaine/diphenhydramine/magnesium topical solution. 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  Thalidomide  Topical antidepressants Opiate Pharmacotherapy  Special issues  Evidence for efficacy The New Millennium Era of “Balance”  Growing recognition that opioids are essential for chronic pain  DEA, FDA, Federation of State Medical Boards, APS, AAPM, ASAM, ACR, AGS  – all issue guidelines supporting appropriate use of opioids for chronic pain  Potential risks are serious but can be managed  The goal: maximize symptom relief and functional improvement while minimizing addiction, diversion, and side effects 6 What Types of Pain May Respond to Opioids? • Categories – – – acute pain cancer pain chronic (persistent) noncancer pain episodic/continuous nociceptive (somatic or visceral) neuropathic (peripheral or central) • Temporal pattern – • Mechanisms – – 9 Acute Pain Management: Continuing Treatment  Clinical lore to the contrary, acute postoperative Challenges pain is poorly controlled.  Persistent acute pain may have harmful physiological and psychological effects.  Agency for Health Care Policy and Research guidelines for treatment of moderate to severe postoperative pain recommend opioid analgesics. 13 Categories of Opioid Drugs  Short-acting opioids – morphine sulfate (eg, Roxanol™, MSIR®) – codeine – hydrocodone (eg, Zydone®, Vicodin®, Lortab®, – – – – 16 Vicoprofen®)* oxycodone (eg, Roxicodone™, Oxy IR®, Percocet®, Tylox®, Percodan®)* hydromorphone (Dilaudid®) oxymorphone (Numorphan®) fentanyl (Actiq®) * May contain additional active ingredient. Categories of Opioid Drugs (cont)  Long-acting opioids – methadone – sustained-release morphine (eg, MS Contin®, Avinza™; Kadian®, Oramorph®) – sustained-release oxycodone (Oxycontin®) – transdermal fentanyl (Duragesic®) 17 Opioids in Chronic Pain: Review of Randomized, Controlled Clinical Trials pain  Efficacy of opioids in chronic noncancer established in a number of randomized, controlled trials, including placebo-controlled trials of: – – – – – codeine tramadol oxycodone morphine fentanyl  Comparative trial of transdermal fentanyl and sustainedrelease oral morphine 18 Assessing and Documenting Treatment Outcomes The “Four A’s of Pain”   analgesia activities of daily living   adverse effects aberrant drug-taking behaviors 20 Reassessment: The Importance of FollowContinual follow-up and monitoring are essential up to good opioid analgesic therapy.  Reassess the “Four A’s of Pain” – – – –  33 analgesia activities of daily living adverse effects aberrant drug-taking behaviors Review treatment options Management of Opioid Side Effects  Nausea and vomiting – switch opioids; anti-emetics  Sedation – lower dose if possible; add co-analgesics; add stimulants  Constipation – treat prophylactically with stool softeners, bowel stimulants, and nonpharmacologic measures; switch opioids 34 Management of Opioid Side Effects (cont)  Itching – switch opioids; antihistamines  Endocrine dysfunction/decrease in libido – switch opioids; endocrine monitoring; testosterone replacement; endocrine consultation  Addiction – refer for comprehensive assessment 35 would arise if a drug is discontinued, dose is substantially reduced, or antagonist is administered  Tolerance: a greater amount of drug is needed to maintain therapeutic effect, or loss of effect over time  Pseudoaddiction: behavior suggestive of addiction caused by undertreatment of pain  Addiction (psychological dependence): a psychiatric disorder characterized by continued 36 compulsive use of a substance despite harm Distinguishing Dependence, Tolerance,  Physical dependence: a withdrawal syndrome and Addiction 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.