1. Pain Management in the Hospital
Rog Kyle, MD
Medical University of South Carolina
2/7/12

2. Objectives
Differentiate acute, chronic, somatic, neuropathic, referred, and visceral pain syndromes.
Differentiate tolerance, dependence, addiction, and pseudo-addiction.
Explain the indications and limitations of non-pharmacological, pharmacological, and adjuvant methods of pain control in the hospitalized patient.
Explain the indications and limitations of opioid pharmacotherapy.
Determine equianalgesic dosing for pharmacologic therapy as needed.

3. Key Messages Chronic pain is a significant problem in the elderly
There are many different mechanisms involved in generation and perception of pain
Both non-opioid and opioid options are available for managing pain.
Different classes of medication and non-pharmacotherapies are available for the management of pain syndromes
Opioids have a narrow therapeutic window and their use must be weighed carefully in the management of chronic, non-cancer pain

4. Types of pain
Tolerance, dependence and addiction
Medications

5. Types of Pain

6. Nociceptive Pain Nociceptors = pain fiber sensitive to noxious stimuli
Somatic – injury to tissues, well localized
Visceral – injury to organs (stretch receptors), poorly localized
Referred – afferent visceral fibers + somatic to same spinothalamic pathway

7. Neuropathic pain
Abnormal neural activity secondary to disease, injury, or dysfunction
Persists without ongoing injury (trigeminal neuralgia, DM neuropathy)
Types:
Sympathetic – from peripheral nerve injury with autonomic changes
“New” term – Complex Regional Pain Syndrome (CRPS)
Type I = RSD
Type II = causalgia
Peripheral autonomic pain –
Same but without autonomic change (PHN)
Central Pain (spinal cord injury)

8. Tolerance, Dependence, Addiction

9. Tolerance
Tolerance - increase the dose to maintain equipotent analgesic effects
Associative - linked to environmental clues and involves psychological factors
Adaptive - involves down-regulation or desensitization of opioid receptors, or both

10. Tolerance Repeated administration of opioids
Desensitization or down-regulation
Sensitization – similar to neuropathic pain with increased sensitivity to pain

11. Can’t distinguish the hyperalgesia due to opioid treatment from the hyperalgesia due to worsening neuropathic pain
It is often impossible to distinguish between pharmacologic tolerance and abnormal pain sensitivity
Both lead to escalation of opioid therapy that ultimately fails

12. Dependence
Rapid discontinuation of opioid following prolonged administration produces symptoms
Dysphoria
Anxiety
Mood volatility
Hypertension
Tachycardia
Sweating

13. Dependence Psychological dependence Physical dependence
Extreme behavior (craving) associated with procuring/consuming drug
High vs. withdrawal
Physical dependence
class-specific withdrawal syndrome that can be produced by abrupt cessation or rapid dose reduction of a drug (or administration of an antagonist)

14. Addiction Physical and psychological dependence
Chronic relapsing disorder characterized by persistent drug-seeking and drug-taking behaviors
Impaired control over use, compulsive use, continued use despite harm and craving

15. Medications

16. NSAIDS

17. Wide variety 60 million Rx’s/yr
Clinical efficacy of equipotent doses is similar
Individual responses highly variable – especially toxicity
cox-1 vs. cox-2
naprosyn may have greatest relative cardiovascular safety profile
diclofenac - available as a topical patch for pain due to trauma and as a gel for treatment of painful joints
sulindac – increased hepatotoxicity
indomethacin - GI and central nervous system adverse effects may be more frequent or severe than with other NSAIDs
ketorolac - risk of gastropathy is increased when use exceeds five days
piroxicam – high GI toxicity
celecoxib – no antiplatelet function. Increased CV risk above 200mg/day

18. Utility of NSAIDS Variations in patient response
Generally indicated in mild to moderate pain
Mostly for pain of somatic origin although has a CNS effect as well
Each trial should last a couple weeks
May have an opioid sparing effect as adjunct
Use at the maximum anti-inflammatory dose
Protein bound – may interfere with other protein bound drugs (dilantin. coumadin)

19. Utility of NSAIDS
Noted variability in the response to NSAIDS between patients
Does not appear related to serum concentrations
Degree of Cox inhibition doesn’t correlate with effect
Non-prostaglandin effects may predominate in some patients
Switching between classes of NSAIDS may be beneficial

20. Tricyclic Antidepressants

21. Utility in pain management
Most useful in neuropathic pain
None of the TCA’s carries an indication for pain management
Used frequently in variety of settings
Amitriptyline most widely studied
Anti-depressant effects may alleviate depression associated with chronic pain
May have synergy with opioids
Switching TCA’s based on effect and/or side effects can be tried…but often frustrating

22. Mechanism of action Generally unknown
Theories involve action on serotonin, norepinephrine receptors (TCAs with the greatest effect upon serotonin seem to have the greatest analgesic effect)
May potentiate endogenous opioid system
However, potent serotonin RI’s have no analgesic effect of their own
Can take weeks to work

23. Side effects Anticholinergic (amitriptyline > nortriptyline)
Also GI, CV, neurologic (esp. sedation – maybe a +’ve)
Anticholinergic and CNS effects may diminish in days to weeks – “ride it out”

24. Anticonvulsants

25. Utility in pain management
Can be very effective, particularly in neuropathic pain
Wide variation in use among pain specialists, except with carbamazepine for trigeminal neuralgia
Gabapentin is frequently a first choice as levels do not need monitoring

26. Mechanism of action
Theories include membrane stabilization (phenytoin), inhibition of repeated neuronal discharges (carbamazepine), GABA inhibition enhancement (valproic acid, clonazepam), GABA mimetics (gabapentin, pregabalin).

27. Adjuvant medications

28. Benzodiazepines
Good choice when anxiety complicates pain management (esp’ly cancer patients)
Clonazepam particularly useful in neuropathic pain (GABA potentiation)
Drawbacks well known
Addictive potential is significant
Potentiates sedation and respiratory depression

29. Antispasmodics
Painful muscle spasm, myoclonic jerks can accompany a variety of pain conditions (and opioids)
toxicity of morphine
Mechanism of action may reflect their sedative effects more than direct muscle effect
Commonly used – cyclopenzaprine, carisoprodol, baclofen, methcarbamol

30. SSRI/SNRI Often tried when TCA side effects limit utility
May be treating depression – not an uncommon consequence of life with chronic pain
Venlafaxine has been shown to be similar to imipramine in one study of painful neuropathy
Duloxetine approved for diabetic peripheral neuropathy
Depression is probably undertreated in chronic pain patients in general (cancer and non-cancer pts)

31. Opioids

32. Opioids
Role in treatment of pain is well established for acute pain, malignant pain and care of the terminally ill
Role in chronic non-cancer pain is more controversial
WHO Ladder

34. Opioids
WHO Ladder
Moderate to severe - fixed dose schedule and not on a “prn” basis
Stepwise approach
Adjuvants useful in enhancing analgesia and controlling side effects

35. Opioids
Equi-analgesic dosing

37. Opioids Equianalgesic dosing Equianalgesic conversion
MUSC pharmacy recommends 50% dose reduction for cross tolerance (others recommend 25-50%) except for methadone and fentanyl (see below)

39. Opioids Equianalgesic dosing Equianalgesic conversion
Methadone conversion ratio

41. Opioids Equianalgesic dosing Equianalgesic conversion
Methadone conversion ratio
Fentanyl conversion

43. Therapeutic failures and adverse outcomes
One of the fundamental principles of pain management is that the dose of an opioid should be increased until maximal analgesia is achieved with minimal side effects
What to do when this doesn’t work?
Identifying causes of treatment failure
Progression of underlying illness
Pharmacologic tolerance
Increased pain sensitivity

44. PCA Efficacy established in post-op pain
Morphine, hydromorphone, fentanyl
Higher pt satisfaction, better pain control, higher amount of opioid overall

45. PCA
Morphine
Metabolites (morphine-6-glucuronide) accumulate in renal failure = sedation, respiratory depression
Fentanyl
Less histamine release = better in hypotension, bronchospasm
Inactive metabolites (hepatic), Safe in ESRD
Hydromorphone
Safe in ESRD
High concentration/low volume

47. PCA Conversion
When converting from a PCA to an oral regimen in patients requiring long term pain control
Give approximately 50% of 24 hr total opioid use as a long acting oral formulation and 50% as breakthrough oral formulation
Reduce dose 25-50% to account for cross tolerance if switching opioid

48. Side Effects Depressed respiratory drive
Depressed consciousness, hallucinations
Hypotension
Nausea, vomiting
Ileus, constipation
Urinary retention

49. Examples – Equianalgesic Dosing
Convert a patient requiring 120 mg of p.o. morphine and 20 mg i.v. morphine to p.o. oxycodone
20 mg i.v. morphine = 60 mg p.o. morphine
120 mg + 60 mg = 180 mg morphine/24 hr
Ratio 3:2 for morphine:oxycodone (po) = 120 mg oxycodone
Reduce by 25-50% = mg oxycodone po Q4H

50. Examples – Methadone Conversion
Convert a patient taking 300 mg MS Contin BID and 60 mg MSIR Q4H to methadone
Total oral morphine/24 hrs = 960mg
Conversion ratio is 16 for 960 mg = 960/16 = 60
Reduce by 50% for cross tolerance = 30
Given Q8H = 30/3 = 10 mg Q8H methadone

51. Examples – PCA to Oral Opioid
Convert a patient with hydromorphone PCA set at basal rate of 1 mg/hr and breakthrough of 0.2mg Q10 min that utilized a total of 6 mg of breakthrough in previous 12 hours to oral oxycodone
24 hr iv hydromorphone use = 24 mg basal (1 mg/hr x 24 hrs) + 12 mg breakthrough (6 mg/12 hrs x 2) = 36 mg hydromorphone IV
oxycodone:hydromorphone iv = 20:1.5 = 480 mg oxycodone
Reduce 50% for cross tolerance = 240 mg oxycodone
Giving 50% of total as long acting = OxyContin 60 mg BID + 20 mg oxycodone Q4H

52. References
Ballantyne JC, Mao J. Opioid Therapy for Chronic Pain. N Engl J Med 2003;349:
Hudcova J, McNicol ED, Quah CS, Lau J, Carr DB. Patient controlled opioid analgesia versus conventional opioid analgesia for postoperative pain (Review). Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD003348
Roelofs PD, Deyo RA, Koes BW, Scholten RJ, van Tulder MW. Nonsteroidal anti-inflammatory drugs for low back pain: an updated Cochrane review. Spine (Phila Pa 1976). 2008;33(16):1766
Von Korff M, Kolodny A, Deyo RA, Chou R. Long-term opioid therapy reconsidered. Ann Intern Med. 2011;155(5):325
Joranson DE, Ryan KM, Gilson AM, Dahl JL. Trends in medical use and abuse of opioid analgesics. JAMA. 2000;283(13):1710
Dobecki DA, Schocket SM, Wallace MS. Update on pharmacotherapy guidelines for the treatment of neuropathic pain. Curr Pain Headache Rep. 2006;10(3):185
Saarto T, Wiffen PJ. Antidepressants for neuropathic pain: a Cochrane review. J Neurol Neurosurg Psychiatry. 2010;81(12):1372

53. References
Ballantyne JC, Mao J. Opioid Therapy for Chronic Pain. N Engl J Med 2003;349:
Hudcova J, McNicol ED, Quah CS, Lau J, Carr DB. Patient controlled opioid analgesia versus conventional opioid analgesia for postoperative pain (Review). Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD003348
Roelofs PD, Deyo RA, Koes BW, Scholten RJ, van Tulder MW. Nonsteroidal anti-inflammatory drugs for low back pain: an updated Cochrane review. Spine (Phila Pa 1976). 2008;33(16):1766
Von Korff M, Kolodny A, Deyo RA, Chou R. Long-term opioid therapy reconsidered. Ann Intern Med. 2011;155(5):325
Joranson DE, Ryan KM, Gilson AM, Dahl JL. Trends in medical use and abuse of opioid analgesics. JAMA. 2000;283(13):1710
Dobecki DA, Schocket SM, Wallace MS. Update on pharmacotherapy guidelines for the treatment of neuropathic pain. Curr Pain Headache Rep. 2006;10(3):185
Saarto T, Wiffen PJ. Antidepressants for neuropathic pain: a Cochrane review. J Neurol Neurosurg Psychiatry. 2010;81(12):1372