1. Pharmacotherapy of Pain: Adjuvant Analgesics

2. Adjuvant Analgesics Defined as drugs with other indications that may be analgesic in specific circumstances Defined as drugs with other indications that may be analgesic in specific circumstances Numerous drugs in diverse classes Numerous drugs in diverse classes Sequential trials are often needed Sequential trials are often needed

3. Adjuvant Analgesics Multipurpose analgesics Multipurpose analgesics Drugs used for neuropathic pain Drugs used for neuropathic pain Drugs used for musculoskeletal pain Drugs used for musculoskeletal pain Drugs used for cancer pain Drugs used for cancer pain Drugs used for headache Drugs used for headache

4. Multipurpose Adjuvant Analgesics ClassExamples ClassExamples Antidepressantsamitriptyline, desipramine, nortriptyline, paroxetine, venlafaxine, citalopram, others Antidepressantsamitriptyline, desipramine, nortriptyline, paroxetine, venlafaxine, citalopram, others Alpha-2 adrenergic tizanidine, clonidine agonists Corticosteroidsprednisone, dexamethasone

5. Multipurpose Adjuvant Analgesics Antidepressants Best evidence: 3 0 amine TCAs (eg, amitriptyline) Best evidence: 3 0 amine TCAs (eg, amitriptyline) 2 0 amine TCAs (desipramine, nortriptyline) better tolerated and also analgesic 2 0 amine TCAs (desipramine, nortriptyline) better tolerated and also analgesic Some evidence for SSRI/SSNRIs/atypical antidepressants (eg, paroxetine, venlafaxine, maprotiline, bupropion, others) and these are better tolerated yet Some evidence for SSRI/SSNRIs/atypical antidepressants (eg, paroxetine, venlafaxine, maprotiline, bupropion, others) and these are better tolerated yet

6. Multipurpose Adjuvant Analgesics Alpha-2 adrenergic agonists Clonidine and tizanidine used for chronic pain of any type Clonidine and tizanidine used for chronic pain of any type Tizanidine usually better tolerated Tizanidine usually better tolerated Tizanidine starting dose 1–2 mg/d; usual maximum dose up to 40 mg/d Tizanidine starting dose 1–2 mg/d; usual maximum dose up to 40 mg/d

7. Adjuvant Analgesics for Neuropathic Pain ClassExamples Anticonvulsantsgabapentin, valproate, phenytoin, carbamazepine, clonazepam, topiramate, lamotrigine, tiagabine, oxcarbazepine, zonisamide, levetiracetam Local anestheticsmexiletine, tocainide

8. Adjuvant Analgesics for Neuropathic Pain ClassExamples NMDA receptor dextromethorphan, ketamine Antagonistsamantadine Miscellaneousbaclofen, calcitonin Topical lidocaine, lidocaine/prilocaine, capsaicin, NSAIDs

9. Adjuvant Analgesics for Neuropathic Pain Anticonvulsants Gabapentin commonly used Gabapentin commonly used –Favorable safety profile and positive RCTs in PHN/diabetic neuropathy –Usual effective dose: 600–3600 mg/d and sometimes higher Analgesic effects established for phenytoin, carbamazepine, valproate, clonazepam, and lamotrigine Analgesic effects established for phenytoin, carbamazepine, valproate, clonazepam, and lamotrigine Limited experience with other drugs Limited experience with other drugs

10. Adjuvant Analgesics for Neuropathic Pain Local anesthetics Local anesthetics Oral therapy with mexiletine, tocainide, flecainide Oral therapy with mexiletine, tocainide, flecainide IV/SQ lidocaine also useful IV/SQ lidocaine also useful Useful for any type of neuropathic pain Useful for any type of neuropathic pain

11. Adjuvant Analgesics for Neuropathic Pain Miscellaneous drugs Calcitonin Calcitonin –RCTs in CRPS and phantom pain –Limited experience Baclofen Baclofen –RCT in trigeminal neuralgia –30–200 mg/d or higher –Taper before discontinuation

12. Adjuvant Analgesics for Neuropathic Pain NMDA-receptor antagonists N-methyl-D-aspartate receptor involved in neuropathic pain N-methyl-D-aspartate receptor involved in neuropathic pain Commercially-available drugs are analgesic: ketamine, dextromethorpan, amantadine Commercially-available drugs are analgesic: ketamine, dextromethorpan, amantadine

13. Topical Adjuvant Analgesics Used for neuropathic pain Used for neuropathic pain –Local anesthetics Lidocaine patch Lidocaine patch Cream, eg, lidocaine 5%, EMLA Cream, eg, lidocaine 5%, EMLA Capsaicin Capsaicin Used for musculoskeletal pains Used for musculoskeletal pains NSAIDs NSAIDs

14. Adjuvant Analgesics for Musculoskeletal Pain “Muscle relaxants” Refers to numerous drugs, eg, cyclobenzaprine, carisoprodol, orphenadrine, methocarbamol, chlorzoxazone, metaxalone Refers to numerous drugs, eg, cyclobenzaprine, carisoprodol, orphenadrine, methocarbamol, chlorzoxazone, metaxalone Centrally-acting analgesics Centrally-acting analgesics Do not relax skeletal muscle Do not relax skeletal muscle

15. Adjuvant Analgesics for Chronic Headache Beta blockers Beta blockers Anticonvulsants Anticonvulsants Calcium channel blockers Calcium channel blockers Alpha-2 adrenergic agonists Alpha-2 adrenergic agonists Antidepressants Antidepressants Vasoactive drugs Vasoactive drugs ACE inhibitors ACE inhibitors

16. Adjuvant Analgesics for Cancer Pain For bone pain For bone pain –Bisphosphonates (eg, pamidronate, clodronate), calcitonin, radiopharmaceuticals (eg, Sr 89, Sm 153 ) For bowel obstruction pain For bowel obstruction pain –Anticholinergics, octreotide

17. Adjuvant Analgesics With Opioid Interactions NMDA antagonists (eg, dextromethorphan, ketamine, amantadine) NMDA antagonists (eg, dextromethorphan, ketamine, amantadine) Cholecystokinin-B antagonists (eg, proglumide) Cholecystokinin-B antagonists (eg, proglumide) Ultra-low doses of opioid antagonists Ultra-low doses of opioid antagonists