A. Pain Sensation [4]

1. Type A Fibers
   1. Type A ß - light touch, hair movement (myelinated)
   2. Type A delta1 - mechanical force (myelinated)
   3. Type A delta2 - thermal, mechanical (± myelination)
2. Type C - polymodal pain fibers (0.5-1.5µm axon diameter)
3. Control of Pain
   1. Goal is generally blockade of Delta and Type C Fibers
   2. This is particularly true for preventing neuropathic pain (compare with cancer pain)
   3. Neuropathic pain may be caused by primary lesion in central or peripheral nerves
4. Neurotransmitters mediating pain or blocking pain
   1. Substance P
   2. Calcitonin Gene Related Peptide (CGRP)
   3. Peripheral and Central Opiates (endorphins) are main pain blockers
   4. Modulating effect by serotonin

B. Cancer Pain Overview [1,2,6,7]

1. Goal is complete eradication of pain with minimal side effects
   1. Frequent evaluation of patient's perspective of pain control is essential
   2. Verbal and visual analog scales are often helpful
2. Combination therapy is often optimal and should be used
   1. Opiates are mainstay of therapy
   2. Adjuvant agents are used to improve pain control and minimize side effects
3. Careful attention to specific side effects is critical
4. Radiation therapy (external or implants) directed at specific lesions can be helpful
5. World Health Organization has established an analgesic ladder for cancer pain therapy
6. Pain Due to Spinal Cord Compression [6]
   1. Back pain in patients with cancer should be evaluated very carefully
   2. Metastases to epidural space may occur in the absence of early symptoms
   3. Magnetic resonance imaging (MRI) is the best tool for evaluation
   4. High dose glucocorticoid therapy is initially therapy of choice in concerning cases
   5. Radiation therapy is indicated for prostate or breast cancers, myeloma or lymphoma
   6. Surgical decompression is advocated for radioresistant cancers

C. Opiates [8]

1. Mainstay of therapy for cancer pain; should be used liberally
2. Prescribing Opioids for Pain
   1. Confirm inadequacy of non-opioid analgesics
   2. Explain benefits and risks and clinic's monitoring policies
   3. Establish treatment goals
   4. Strongly consider written consent or contract (inform on toxicology screening also)
   5. Initiate therapy at low standard dose and increase as tolerated up to 8 weeks
   6. Constipation prophylaxis is critically important and often overlooked
   7. Maintain stable, moderate, effective dose with monthly refills
   8. Prescriptions should ALWAYS be picked up by patient IN PERSON
   9. Toxicology screening as needed
   10. Comprehensive followup at least once annually
   11. If treatment is failing, slow weaning is critical to prevent acute withdrawal
   12. Dose escalation should be accompanied by careful evaluation of disease progression
   13. If dose escalation fails, opioid rotation may be effective (start new drug at lower dose)
   14. Can also wean and discontinue therapy, restart opioid after abstinence if needed
3. Partial Listing of Agents
   1. Morphine Sulfate:
   2. Dilaudid: high potency
   3. Fentanyl patch and buccal / transmucosal
   4. Oxycodone
4. Side Effects
   1. All (opiate agonists) have similar side effects
   2. Constipation
   3. Lethargy and confusion
   4. Respiratory depression
   5. Obtundation
5. Morphine
   1. Forms: elixir, immediate release (IR), and sustained release (MS Contin®)
   2. Most patients should be taking sustained release and use IR for breakthrough pain
   3. Adjuvant treatments are usually required and can help minimize sedative risks
6. Fentanyl, Transdermal (Duragesic®) [9]
   1. Synthetic opiate anesthetic with short half life when given intravenously (IV)
   2. Patch formulation has half life ~18 hours with onset of action 6-12 hours
   3. Dosages available 25-100µg/hr patches
   4. Side effects similar to other opiates
7. Fentanyl, Transmucosal / Buccal (Actiq®, Fentora®) [5]
   1. Actiq is transmcosal lozenge, dose 200-1800µg, onset ~15 minutes
   2. Fentora is buccal tablet, dose 100-800µg, onset 10-15 minutes
   3. For treatment of breakthrough cancer pain in opiate-toler
8. Anti-constipation interventions including medicines should be instituted
9. Nausea associated with opiodes may be reduced by changing the agent
   1. Sustained release oxycodone is less nauseating than morphine
   2. Transdermal fentanyl bypasses the gastrointestinal tract is is usually well tolerated

C. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

1. NSAID activity for cancer pain most likely because inflammatory component
2. Combination NSAIDs + Opiates appears synergistic for pain
3. Long acting NSAIDs recommended: naproxen, diclofenac, nabumetone
4. Trilisate is weak, but safe and well tolerated (500-1500mg bid-tid)
5. Cox-2 specific inhibitors are the safest chronic agents (celecoxib, rofecoxib)

D. Adjuvant Therapies [7]

1. Should be added to standard pain medications to improve pain control, reduce doses
2. Types of Adjuvant Treatments
   1. General purpose - glucocorticoids, psychostimulants, antihistamines, neuroleptics, muscle relaxants
   2. Neuropathic pain - antidepressants, anticonvulsants, benzodiazepines, others
   3. Bone Pain - glucocorticoids, bisphosphonates, radionucleides, calcitonin
3. Glucocorticoids
   1. Reduce inflammation
   2. May be very effective in some patients for general and/or bone pain
   3. Prednisone or dexamethasone are used
   4. Monitoring for side effects is important if long term use contemplated
   5. Also very effective for reducing pain due to malignant spinal cord compression
4. Tricyclic Antidepressants
   1. Requires days to weeks to work
   2. Good adjuvant activity
   3. Some agents are sedating, and should be used at night
   4. Can improve sleep as well as pain
   5. Paroxetine, amitriptyline, nortriptyline, or desipramine qhs
5. Anticonvulsants
   1. Good activity for neuropathic pain syndromes
   2. Usually carbamazepine (Tegretol®), clonazepam (Klonopin®) or diazepam (Valium®)
6. Miscellaneous Agents
   1. Mexilitine
   2. Calcium channel blockers - verapamil, nifedipine
   3. Alpha-adrenergic blockers - prazosin
   4. NMDA Receptor Blockers - dextromethorphan, ketamine
   5. Secretory agents - octreotide

E. Bone Pain

1. Major concern in cancer patients
2. Probably the most important and devastating aspect of cancer pain
3. Usually multiple sites are involved
4. Single or a few sites may respond to lacolized irradiation
5. Opiate therapy usally with NSAIDS ofen required
6. Pamidronate [10]
   1. Reduces bone pain in breast cancer patients
   2. Also reduces new metastatic lesions and may improve survival
7. Radioisotopes and Bone Pain [11]
   1. Cancer bone pain significantly decreased by 89-Strontium Chloride (Metastron®)
   2. Localizes with Calcium to areas of greatest osteogenic activity
   3. Decay by ß-emission
   4. Pain control usually begins 7-20 days
   5. Studied most in metastatic prostate cancer
   6. Given by slow iv infusion as single dose (90 d interval dosing period)
   7. Side effect is myelosuppression
   8. Samarium-153 lexidronam (Quadramet®) now approved for osteoblastic bone pain [12]
8. N-Type Calcium Channel Blocker (CCB) [13]
   1. Ziconotide (SNX-111, Prialt®) is given intrathecally for severe pain
   2. Has shown good activity in cancer and AIDS associated pain
   3. Active in pain unresponsive to opioids or in patients with severe opioid side effects
   4. Initial dose up to 2.4 micrograms/day (0.1microgram/hour); max 0.8micrograms/hour
   5. ~50% response to ziconotide versus 17% with placebo

References

1. Portenoy RK and Lesage P. 1999. Lancet. 353(9165):1695
2. Levy MH. 1996. NEJM. 335(15):1124
3. Treatment of Cancer Pain. 1993. Med Let. 35(887):1
4. Markenson JA. 1996. Am J Med. 101(1A):6S
5. Fentanyl Buccal Tablet. 2007. Med Let. 49(1270):78
6. Abrahm JL. 1999. Ann Intern Med. 131(1):37
7. Foley K. 1999. JAMA. 281(20):1937 (Case Discussion)
8. Ballantyne JC and Mao J. 2003. NEJM. 349(20):1943
9. Fentanyl. 1992. Med Let. 1992. 34(881):97
10. Hortobagyi GN, Theriault RL, Porter L, et al. 1996. NEJM. 335(24):1785
11. Radioactive Strontium. 1993. Med Let. 35(908):102
12. Radioactive Samarium. 1997. Med Let. 39(1008):83
13. Staats PS, Yearwood T, Charapata SG, et al. 2004. JAMA. 291(1):63