1. Pain Management
Dr. Lamya Alnaim

2. Pain is a Very Significant Problem
Pain has negative effects on sleep, work, enjoyment of activities, sexual function, and personal interactions
Multiple studies show pain of all types is under treated

3. Pain is a Very Significant Problem
Good medications and treatments are available
Barriers (patient and caregiver) include lack of education, attitudes (myths, cultural differences), and regulatory/legal issues

4. Definition: Acute Pain
An unpleasant sensory and emotional reaction/sensation secondary to tissue damage
Arises from injury, trauma, spasm, or disease of the skin, muscles, somatic structure or viscera.
Corresponds to the degree of injury
Self limiting- limited duration

5. Definition: Acute Pain
Serves a purpose
By inducing an organism to withdraw from or avoid a noxious stimulus.
Responds to conventional therapy.
Decreases in intensity as the damaged area heals and tissue repair takes place.

6. Definition of Chronic Pain
Any pain that
Persists beyond the expected time after a physical or emotional injury
Subjective complaints are magnified
Pain is out of proportion to clinical signs
Is accompanied by severe psycho-social issues
Responds poorly to conventional therapy

7. Persistent Pain PAIN SUFFERING DEPRESSION LOSS OF FUNCTION DRUG ABUSE
FINANCIAL LOSS
DOMESTIC DISRUPTION

8. Who Gets Persistent Pain ?
Systemic disease
Diabetes mellitus
hypothyroidism
HIV/AIDS
Hepatitis C
Malignancy
Neurological disease….ALS, MS
Rheumatoid related syndromes
Obesity Psychiatric co-morbidity

9. ACUTE PAIN CHRONIC PAIN Meaningful, linear, reversible
Well defined, recent onset, clear definable cause
Observable responses
Readily responds to analgesics
Usually nociceptive in origin
CHRONIC PAIN
Meaningless, cyclical, irreversible
Persists over time
Adaptation
Less amenable to analgesics alone
Multiple etiologic components

10. Cancer Pain 20-50 % at time of diagnosis
Incidence varies with tumor type
55-95% with advanced disease
50-70% report pain of moderate to severe intensity
30% report excruciating pain

11. Pain Experience in Ambulatory Cancer Patient Population

12. Pain Classification Schemes
1-Neurophysiologic:
Nociceptive (somatic, visceral)
Neuropathic
2-Duration: acute vs. chronic
3-Temporal pattern:
continuous
intermittent
incident
Breakthrough
End-of-dose failure

13. Pain Classification Schemes
4-Severity
5-Specific cancer pain syndromes (etiology):
Tumor infiltration of bone, nerve, viscera.
Treatment related.

14. Types of Persistent Pain
Nociceptive
Musculo skeletal
Joint
Ligamentous
Visceral
Neuropathic
Central
Somatic
Sympathetic
Psychogenic
Mixed

15. Types of Pain: Nociceptive vs. Neuropathic
Mediated by normal nervous system:
Inflammatory pain: in response to activation of peripheral nociceptors by either mechanical pressure, high or low temperature or chemical mediators.
Usually acute

16. Types of Pain: Nociceptive vs. Neuropathic
Somatic –
arising from skin, bone, joint, muscle, or connective tissue
dull, aching, well-localized. Bone metastasis, invasion of soft tissue

17. Types of Pain: Nociceptive vs. Neuropathic
Visceral –
vague distribution, referred. Bowel obstruction, carcinomatosis, pleural effusion
arising from internal organs such as the large intestine or pancreas

18. Types of Pain: Nociceptive vs. Neuropathic
mediated by damaged nervous system:
Localized to an area of sensory abnormality
Pain in response to non-painful stimuli
Pain in the absence of ongoing tissue damage
Painful peripheral neuropathy, post mastectomy pain, brachial plexopathy

19. Nociceptive vs Neuropathic Pain
Caused by activity in neural pathways in response to potentially tissue-damaging stimuli
Mixed Type
Caused by a combination of both primary injury and secondary effects
Neuropathic Pain
Initiated or caused by primary lesion or dysfunction in the nervous system
CRPS*
Postherpetic neuralgia
Postoperative pain
Nociceptive, or inflammatory, pain is pain resulting from activity in neural pathways caused by potentially tissue-damaging stimuli.1 Examples include postoperative pain, arthritis, mechanical low back pain, sickle cell crisis, and sports or exercise injuries.
Neuropathic pain is pain caused by a primary lesion or dysfunction in the peripheral and/or central nervous systems.2 Examples of peripheral neuropathic pain syndromes include HIV sensory neuropathy, postherpetic neuralgia (PHN), and diabetic neuropathy. Examples of central neuropathic pain include central poststroke pain, spinal cord injury pain, trigeminal neuralgia, and multiple sclerosis pain.
As indicated by the “mixed type” area on the slide, chronic pain can be of mixed etiology with both nociceptive and neuropathic characteristics.
Two types of neuropathic pain—PHN and diabetic neuropathy—will be emphasized within this module. These types of pain are being stressed because the great majority of randomized controlled trials of treatments for neuropathic pain have examined these two disorders, and because our understanding of the mechanisms of neuropathic pain is largely derived from those studies.
1. Portenoy RK, Kanner RM. Definition and Assessment of Pain. In: Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice. Philadelphia, Pa: FA Davis Company; 1996:4.
2. Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain. Minneapolis, Minn: The McGraw-Hill Companies Inc; 2000:8-9.
Arthritis
Trigeminal neuralgia
Sickle cell crisis
Neuropathic low back pain
Mechanical low back pain
Central post- stroke pain
Sports/exercise injuries
Distal polyneuropathy (eg, diabetic, HIV)
*Complex regional pain syndrome.

20. Nociceptive, or inflammatory pain is pain resulting from activity in neural pathways caused by potentially tissue-damaging stimuli. Examples include postoperative pain, arthritis, mechanical low back pain, sickle cell crisis, and sports or exercise injuries.

21. Neuropathic pain is pain caused by a primary lesion or dysfunction in the peripheral and/or central nervous systems. Examples of peripheral neuropathic pain syndromes include HIV sensory neuropathy, postherpetic neuralgia (PHN), and diabetic neuropathy. Examples of central neuropathic pain include central poststroke pain, spinal cord injury pain, trigeminal neuralgia, and multiple sclerosis pain.

22. As indicated by the “mixed type” area on the slide, chronic pain can be of mixed etiology with both nociceptive and neuropathic characteristics

23. Manifestations of Pain
Acute
Increased BP, P, R.
Dilated pupils.
Sweating.
Focuses on pain
Reports pain
Crying, moaning
restless
Grimace
Chronic
Normal
Dry skin
Easy distraction
No report
Quiet, sleep, rest
Blank or normal facial expression
Behavioral Physiologic

24. Key Principles in Assessment
Pain is a multidimensional, subjective, and uniquely personal experience
Pain is what ever the person says it is, occurring whenever the person says it does
Reliance on observable physiologic and behavioral manifestations in order to verify existence and severity of pain is inadequate
Physiologic: etiology.
Sensory: location, intensity, quality.
Affective: mood states, locus of control.
Cognitive: meaning of pain and suffering.
Behavioral: communication of pain, medication use.
Sociocultural: variation in demographic-ethnic expression of pain, learned expressions.

25. Goals of Assessment
Estimate severity of pain (0-10 scale, visual analog scale)
Form clinical impression regarding etiology
Determine need for additional diagnostic testing
Formulate therapeutic recommendations which take into account the patient’s medical and psychosocial status

26. Symptom Assessment Impact of function and QOL. Site Onset
Impact on psychological state.
Response to prior therapy.
Treatment preferences.
Site
Onset
Temporal pattern
Quality
Relieving/Provoking factors
Associated signs/ symptoms

27. Pain Intensity Rating Scales
Visual Analogue Scale (VAS)
No pain Worst pain
Numerical Rating Scale 10
No pain
Worst pain imaginable
A number of excellent unidimensional tools exist that measure only pain intensity and have the advantages of being brief, easy to administer, and sensitive to treatment effects. Such tools include a visual analog scale (VAS), most often a 10-cm line anchored at one end by the description “no pain” and at the other end by “worst possible pain,” on which the patient marks the line at the point that best describes their pain intensity. Also used is a numerical rating scale (NRS) [“On a scale of 0 to 10, in which 0 is no pain and 10 is the worst pain imaginable, how severe is your pain?]. The categorical scale allows the patient to choose from four categories of intensity, from “none” (0) to “severe” (7-10).
Cleeland, CS. Pain Research Group University of Texas M.D.Anderson Cancer Center. BPI Copyright 1991.
Jacox A, Carr DB, Payne R, et al. Management of Cancer Pain. Clinical Practice Guidelines No. 9. AHCPR Publication No Rockville, MD. Agency for Health Care Policy and Research, U.S. Department of Health and Human Services. Public Health Service, March 1994.
Cleeland
Categorical Scale
None (0) Mild (1 – 4) Moderate (5 – 6) Severe (7 – 10)

28. Guidelines in Pain Therapy
Assess the pain frequently
Pain assessment must be dynamic and not static
Use around the clock therapy (ATC)
Treat and assess breakthrough pain aggressively
Where possible use oral route
Consider age, previous drug usage, hepato- renal function
Monitor for abuse
Monitor and treat side effects

30. Treatment Goals Decrease Intensity and duration of pain
Decrease conversion from acute to chronic
Decrease suffering and disability
Decrease psychological and socioeconomic of sequel of untreated pain.

31. Treatment Goals Optimize drug therapy
Improve quality of life and optimize ability to perform activities of daily living
Minimize adverse effects of therapy
Minimize inappropriate use

32. Overall Treatment Strategies
Analgesic and adjuvant medications
Physical therapies
Psychological interventions
Anesthetic and neurolytic procedures

33. WHO Three-Step Analgesic Ladder
Step 1: Mild pain
Non-opioid, + Adjuvant
Step 2: Mild to moderate pain
Opioid for mild to moderate pain, + non-opioid, + Adjuvant
Step 3: Moderate to Severe Pain
Opioid for moderate to severe pain , + non-opioid, + Adjuvant.
Titrate medication and dose to pain type
and intensity individualizing treatment.
Medication
Dose
Route
Interval
Use a preventative approach.

34. WHO Analgesic “Ladder” for Cancer Pain
Freedom from Pain
Proposed 4th Step
Intrathecal Opioid Delivery
Pain persisting or increasing
Step 3 Opioid for moderate to severe pain ± Nonopioid ± Adjuvant
WHO 3-Step
Analgesic
Ladder
Pain persisting or increasing
Step 2 Opioid for mild to moderate pain ± Nonopioid ± Adjuvant
Revised WHO Analgesic “Ladder” for Cancer Pain
To optimize cancer pain therapy, the World Health Organization (WHO) has established a simple 3-step “ladder” approach, beginning with nonopioid drugs and progressing to stronger opioids as necessary. Adjuvant drugs, such as antidepressants and anticonvulsants, may be used at each step.
In step 1, patients who have mild to moderate pain and are receiving no analgesic therapy should receive nonopioid analgesic drugs, including NSAIDs.
Step 2: If the patient’s mild to moderate pain persists despite therapy with nonopioid analgesic drugs, then the dose of the nonopioid should be increased and mild opioid analgesic drugs added.
Step 3 of the analgesic ladder includes potent opioids, with morphine as the prototype.
Approximately 5% to 15% of patients will continue to have inadequate pain control with this approach. For that reason, a fourth step has been proposed.
This step would add intrathecal pain therapy for patients whose pain is not controlled by oral opioids or for patients who cannot tolerate opioid side effects.
Pain persisting or increasing
Step 1 ± Nonopioid ± Adjuvant
Pain
Deer T, Winkelmuller W, Erdine S, et al. Intrathecal therapy for cancer and nonmalignant pain: Patient selection and patient management. Neuromodulation 1999;2:55-66.

35. Revised WHO Analgesic “Ladder” for Cancer Pain
Approximately 5% to 15% of patients will continue to have inadequate pain control with this approach. For that reason, a fourth step has been proposed.
This step would add intrathecal pain therapy for patients whose pain is not controlled by oral opioids or for patients who cannot tolerate opioid side effects

36. Algorithm for Medication Selection in Various Pain Syndromes
Cancer

38. Cancer Pain
Cancer: Tumor expansion, nerve compression, infiltration by tumor, malignant obstruction, infection of malignant ulcers.
Treatment: radiation → mucositis pain

39. Principles of Analgesia for cancer-Related pain
Follow WHO Ladder
ATC dosing for continuous pain
Rescue dosing for intermittent pain
Oral route unless contraindicated
No PRN
It is reactive not preventive
Requires larger doses to reestablish control which may lead to side effects

40. Principles of Analgesia for cancer-Related pain

41. ATC dosing
Small fixed doses on a schedule to prevent pain

42. Rescue (Breakthrough) dosing
Fixed doses on a flexible schedule
Analgesia is administered in response to pain or to prevent predictable pain
Key to success of pain management
Similar to NG in angina
Use immediate release opioid or NSAIDs

43. Calculating Rescue dosing
25-50% of the 4hrly ATC
If ATC is 60 mg MS q 4 hrs, rescue can be 15 mg
2-5% of the 24 hr ATC dose
Based on response, 50% relief from 2 mg morphine →4 mg should provide ≈ 100% relief
All rescue should be prescribed q 4 hrs

44. Titrating dosage If 3 or more rescue doses in 24 hr
Calculate ↑ based upon total opioid dose ( ATC+ rescue) taken in the previous 24 hrs.
↑ both the ATC and breakthrough
Increase by the following guidelines
Pain > 7 , ↑ dose by %
Pain 4-7, ↑ dose by 25-50%
Pain < 4, ↑ dose by 25%
When patient uses < 2 rescue, sustained release opioid should be started

49. Non Opioid Analgesics
NSAIDS
Acetominophen

50. NSAIDS Mechanism of action Inhibition of prostaglandin synthesis
Synergism with opioid analgesics
Mild to moderate pain
Different side effect profile from opioids
No tolerance or dependence
Ceiling effect
Limited routes

51. NSAIDS Pain from injury, surgery, trauma, arthritis, or cancer
Very effective for bone pain
Predominant effect on PNS→synergistic
All are equipotent
Patient response varies

52. The Arachidonic Acid Cascade and COX-1 and COX-2 Inhibition
Traditional NSAID
Selective COX-2 Inhibitor X
Prostaglandin synthase is the enzyme that converts arachidonic acid into various forms of prostaglandins and is available in two distinct forms: COX-1 and COX-2.
Traditional NSAIDs inhibit both forms of the enzyme, causing a beneficial decrease in pain and inflammation but an adverse alteration in normal body homeostasis.
When COX-2–specific inhibitors were developed, it was hoped that they would inhibit only the COX-2 enzyme, resulting in a reduction in pain and inflammation without the adverse effects due to COX-1 inhibition.1
Fitzgerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med. 2001;345:
Body Homeostasis
Gastric integrity
Renal function
Platelet function
Inflammation
Pain

53. The COX 2 Inhibitors Rofecoxib 25-50 mg daily (Vioxx) →W
Celecoxib mg daily (Celebrex)
Valdecoxib mg daily (Bextra) →W
Etrocoxib
Paracoxib (iv use)

54. The COX 2 Inhibitors Minimal effect on
Gastric integrity
Renal function
Platelet function
Potent inhibition of PGI2 →↑ risk if CV events (MI)

55. Contraindications to COX2 I
Previous side effects with COX2 inhibitors
Allergy to sulpha drugs
History of previous GI bleed
pregnancy
History of perforated gastric ulcer
Esophageal varices
Bronchospastic disease
Renal dysfunction
Coronary artery disease needing aspirin
Congestive heart failure

56. Acetaminophen Same analgesic potency as ASA
No neuropsychological and little GI SE
Orally, or rectally
For musculoskeletal or visceral pain
Can be used in 3 ways
ATC 1g q 4 hrs as 5 doses in 24 hrs
As rescue with ATC opioid 1g q4 PRN
As an adjuvant analgesic
Acetaminophen (APAP) is an effective analgesic by itself. A meta-analysis by Moore et al showed that 1000 mg of acetaminophen in the post-operative patients with moderate to severe pain will decrease the pain by 50% for >4 hours in 18% of patients. This is defined as the numbers-needed-to-treat (NNT). Acetaminophen has long been promoted as a safe analgesic with the potential of toxicity being downplayed or even ignored. The potential for this largely unrecognized toxicity, however, is the reason that the package insert recommends £ 4 grams per day, while long-term therapy has a recommendation of < 3.2 grams per day for a healthy adult and < 2.4 grams per day for elderly, debilitated or malnourished patients.1
The literature identifies many risk factors for APAP toxicity. However, even normal patients can have complications after routine surgery. In fact, a recent study showed that 38% of liver failure cases were linked to acetaminophen compared to only 18% of cases caused by other medications.2 Dr. Lee, therefore, recommended that the total dose of acetaminophen not exceed 2 grams (4 extra-strength pills) in one 24-hour period. This study and others like it have prompted an FDA review of acetaminophen safety guidelines and warnings.
One example of this was identified by Csete and Sullivan in a 19-year-old woman who had an exploratory laparoscopy. On day two, 1-2 Vicodin were administered q4h PO as needed. She took 40 doses in 4 days. As a result, she developed hypoglycemia, metabolic acidosis, abnormal liver enzymes, and bleeding. The young woman died prior to liver transplant.3 This clearly demonstrates that physicians must consider the potential risks of acetaminophen before initiating treatment to any patient, not just those with hepatic compromise.
Moore A, Collins S, Carroll D, McQuay H. Paracetamol with and without codeine in acute pain: a quantitative systematic review. Pain 1997 Apr;70(2-3):
Ostapowicz G, Lee WM. Acute hepatic failure: a Western perspective. J Gastroenterol Hepatol  2000 May;15(5):480-8. 
Csete M, Sullivan JB. Vicodin-induced fulminant hepatic failure. Anesthesiology 1993;79(4):

57. Opioids Strong Opioids Partial agonists Weak opioids Morphine Sulphate
Hydromorphone (Dilaudid)
Demerol
Fentanyl
Methadone
Buprenorphine
Pentazocine
Oxycodone (Roxycodone, Tylox, Percocet)
Hydrocodone (vicodin, lortab, Norco)
Propxyphene ( Darvon, Darvocet)
Codeine
Strong Opioids
Partial agonists
Weak
opioids

58. Opioids
Opioid Agonist: bind w/ opioid receptor site in PNS & CNS = pain relief
No Ceiling
Titrate to pain relief or side effects
Opioid Antagonist: blocks relief. Naloxone
Opioid Agonist-antagonist: + pain relief. Stadol, Nubain, Talwin (not recommended)

59. Opioids
No rationale for combining two opioids, use same agent for ATC and rescue pain.

61. Potent Opiates: Morphine, Hydromorphone.
µ-receptors, κ-receptors
Treat acute, chronic, sever, or terminal malignant pain
Orally, rectally, IV Infusion, epidural , intrathecal
Immediate release analgesic effect 4 hrs

62. Morphine, Hydromorphone.
Doses according to
Prior exposure
Pain severity
Hepatic, renal function
Route of administration
Oral: parental, 5:1

63. Morphine Opioid of choice
Available in multiple routes and formulations
Extensive clinical experience in dosing, route change and side effects.

64. Meperidine…….Demerol Used for traumatic and postoperative pain
1/10 potency of morphine
Oral or parenteral
Short acting
Toxic metabolites: nomeperidine
Can accumulate in renal dysfunction and cause CNS stimulation and seizures
Metabolites with long half life >12 hrs
High addiction potential
Expensive

65. Methadone Equivalent potency to morphine
Orally, IV, rectally, epidurally/intrathecally
Long acting
adjust dose q 5-7 days
Lower addiction and tolerance potential
Cheap
No active or toxic metabolites
8-12 hour analgesic action ( give Q8-12 hrs)
Longer intervals in hepatic failure

66. Methadone CNS depression lasts for 36 hrs after overdose
Needs CIVI Naloxone for reversing effect.
No renal excretion
Dependence on hepatic function (p-450)
Watch for drug-drug interaction

67. Fentanyl >100 potent than morphine
IV, intraspinally as preoperative anesthetic agent
Rapid onset, short duration of action
Transdermal patch: Consistent dosing
Oral lollipop

68. The Fentanyl Patch Indications for use Beware
Severe nausea and vomiting
Unable to swallow
Children
Patients with poor compliance
Concern of drug diversion
Beware
Opioid naïve
Febrile patient
Elderly
Drug abuser

69. The Fentanyl Patch disadvantages 25,50,75,100 mcg Duration 72hrs
Delay in onset of analgesia
Residual activity after the patch is removed
25,50,75,100 mcg
Duration 72hrs
Steady state requires 24 hrs, use supplemental short acting to cover initial period.

71. Weak Opioids Codiene, oxycodone, propoxyphene
For mild to moderate pain

72. Oxycodone Analgesic effect 4 hrs High bioavailability compared to MSO4
No toxic metabolites
Less tolerance compared to MSO4
Higher incidence of euphoria
Expensive

73. Tramadol
Activity against opioid and serotonergic and noradrenergeric pathways in CNS.
Moderate to sever pain
Advantages
Lower abuse liability
Lower risk of respiratory depression
Disadvantages
Dizziness, dry mouth, sedation, constipation.
Use lower doses in elderly

74. Oral Opioid Comparison
Long track record
No toxic metabolites
Formulations
Immediate release
Combinations
Acetaminophen
Ibuprofen
Sustained release
Controlled release
Hydrocodone
Hydromorphone
Oxycodone
When looking at the classic opiates for post-operative use, it becomes evident that individual differences in the analgesic and side effect profiles can be related to their individual metabolite cascades. Morphine and codeine have a 6-glucuronide metabolite, which has been implicated in nausea, itching, sedation, respiratory depression and confusion. The non-6-glucuronide class consists of the agents oxycodone, hydromorphone and hydrocodone. All of these agents have a long track record and avoid the term morphine and its “societal” implications. These agents have no toxic metabolites.
While morphine is a potent immunosuppressant, oxycodone and hydromorphone display no such effects, in vitro. As discerned by Sacerdote and colleagues in Milan, this advantage is directly related to their chemical structure. This, however, has never been tested in humans.
Sacerdote P, Manfredi B, Mantegazza P, Panerai AE. Antinociceptive and immunosuppressive effects of opiate drugs: a structure-related activity study. Br J Pharmacol 1997 Jun;121(4):

75. Equianalgesic Dosing 3-5 .75 200 130 Codeine 4-6 Hydrocodone 2-4 4 300
Meperidine 15
Oxycodone
3-6 5
7.5
1.5
Hydromorphone
4-5 3 30 10
Morphine
DURATION
RATIO PO IV
MEDICATION

76. Dose Conversion Equianalgesic dose of current opioid
24 hrs dose current opioid
Equianalgesic dose of desired opioid
24 hrs dose current opioid =

77. Drug Delivery
No evidence that other routes are superior or have less SE.
Choice of route depends on pragmatic consideration e.g. inability to swallow
Can only be done safely with knowledge of equianalgesic dosing.

78. Oral Route of choice Simple, noninvasive
Reasons for failure: inadequate dose, parenteral to oral conversion made too quickly, dosing intervals too long
Formulation and dose dependent upon pattern of pain and severity
Long Acting Combined with Short Acting for Chronic Pain

79. Sublingual, buccal Simple, noninvasive
Unable to tolerate oral dosing, unable to swallow rapid onset, drug not subject to first-pass effect
fentanyl

80. Intravenous
Most efficient for rapid titration, dose finding, immediate analgesic effect.
Bolus, continuous, PCA.
Steady state better maintained with CI.
Full effects of increase CI will not be felt until steady state or approximately 5-6 half-lives. Therefore with IV Morphine hours.
Morphine, hydromorphone, fentanyl, methadone

81. Rectal Morphine, hydromorphone Conversion from oral at 1:1 ratio
Sustained release tablets of morphine can be used by this route.

82. Subcutaneous Morphine, hydromorphone
Equivalent to IV in efficacy and side effects

83. Conversion to Oral Calculate total daily requirement with PCA
Convert to IV morphine
Convert to Oral morphine
Convert to alternate opioid
75 % as ATC 25% as rescue

84. Prior to Oral Conversion
Patient able to tolerate oral fluids
Oral therapy started prior to removal of PCA
Pain control predictable and stabilized
IV to oral conversion calculated
Side effects under control

85. Example of Conversion Total morphine for 24 hours on PCA= 60mg
Want to convert to Oxycodone.
60 mgm of MS IV( x 3) = 180 mgm oral.
To convert to oxycodone x by 1.5 = 120 mg oxycodone
75% as ATC = 90 mg = 40 mg Q 12 , but factor in 50% less for ICT = 20 mg q 12 hourly
25% as rescue = 30 mg or 5 mg Q 4-6 hourly PRN

86. Calculating SR Opioid
Patient needs 4 mgm per hour Morphine PCA to be pain free.
= 24X4
= 96 mgm per day iv
= 96x3 = 280 mgm oral
75% is given as SR = 200 mgm
25% is given as rescue =80 mgm
To convert to oxycodone X by 1.5
280x1.5 = 140 mgm of oxycodone

87. One 25 mcg/h transdermal fentanyl
Conversion Chart for Starting Dose
of Transdermal Fentanyl
Fixed-combination short-acting opioids (6/day):
Lorcet 5 mg/500 mg
Lortab 5 mg/500 mg
Percocet 5 mg/325 mg
Percodan 5 mg/325 mg
Tylenol + Codeine 30 mg/325 mg
Tylox 5 mg/500 mg
Vicodin 5 mg/500 mg
Long-acting opioids(2/day):
OxyContin 20 mg
MS Contin 30 mg
One 25 mcg/h transdermal fentanyl
patch/3 days (72 hours)
Multiple patches may be used for doses exceeding 100 mcg/h. Doses up to 6oo mcg/h have been evaluated in clinical trials.

88. Renal Failure Methadone Dilaudid Oxycodone Hydrocodone Morphine
Fentanyl
Demerol
NEUROTOXICITY
SEDATION
TOLERANCE

89. All pretty much OK, but halve dose
Liver Failure
Methadone
Dilaudid
Oxycodone
Hydrocodone
Morphine
Fentanyl
Demerol
All pretty much OK, but halve dose

90. Side effects of opioids
Constipation
Sedation
Mental clouding
Respiratory depression
Nausea and vomiting
Orthostatic hypotension
Urinary retention
Pruritus
Myoclonus

91. Constipation Tolerance does not develop
Dose dependent
Preventative approach
Bulk and stimulant laxatives
Decreased gastric, pancreatic, biliary secretions.
Decrease motility
Delayed passage

94. Sedation Strategies: change dose, frequency, type of opioid
Common with start, increase, change drug, pain relief in sleep deprived.
Tolerance to sedative effects 2-7 days.
Other causes: sedatives, sepsis, metabolic imbalances, hypoxia.
Strategies:
change dose, frequency, type of opioid
Stimulants: Caffeine, dextroamphetamines, methylphenidate

95. Respiratory Depression
Direct action on brain stem respiration receptors; decreased responsiveness to CO2 levels
Pain is physiologic antagonist
Risk factors
Rapid tolerance
Short acting
Goal: gradual reversal without analgesic withdrawal
Naloxone 0.4 mg/10cc; 0.5 cc q 2-3 mins

96. Nausea - Vomiting Common with start or increase dose
Tolerance within 2-3 days
Rule out other causes
Treatment:
treat constipation, use antiemetics, change opioid

97. Withdrawal Physical dependence
Causes: abrupt discontinuation, rapid dose reduction, antagonist, agonist- antagonist
Onset dependent upon elimination half-life
Signs and symptoms
25% of daily dose

98. Dependence Physical dependence Psychological dependence
Pseudo addiction

99. Definitions
Physical Dependence: involuntary, adaptation, withdrawal with abrupt reduction or discontinuation
Psychological Dependence (addiction): compulsive use despite harm, for effects other than pain relief

100. Adjuvant Medications Enhance analgesic effect of opioids
Treat concurrent symptoms
Provide independent analgesia
Antidepressants
Neuroleptics
Anticonvulsants
Local anesthetics
Antispasmodics
Muscle relaxants
Psychostimulants
Corticosteroids
NMDA receptor antagonism
Anticholinergics
Bisphosphonates

103. Antidepressant TCA, MAOIs, Clinical effects TCA more easier to use
Improve mood
Improve sleep
Anoxiolytics
Decreased pain perception
TCA more easier to use

104. Antidepressant TCA inhibit reuptake of serotonin and norepinephrine
Serotogergic processes are part of endogenous pain inhibitory mechanisms
TCA have analgesic properties related to ability to increase pain tolerance
Faster onset than antidepressant effect
Have local anesthetic properties

105. Antidepressant
Improve sleep disturbances and depression associated with chronic pain.
1-3 weeks for effect
Amitriptyline most commonly used for painful conditions mg/day
Anticholinergic side effects

106. TCA: Adverse Effects
Commonly reported AEs (generally anticholinergic):
blurred vision
cognitive changes
constipation
dry mouth
orthostatic hypotension
sedation
sexual dysfunction
tachycardia
urinary retention
Fewest AEs
Desipramine
Nortriptyline
Imipramine
Doxepin
Amitriptyline
Adverse effects commonly reported with tricyclic antidepressants (TCAs) are anticholinergic effects, which are listed on the left side of the slide. The adverse effects include blurred vision, cognitive changes (such as concentration, memory loss, and confusion), constipation, dry mouth, orthostatic hypotension, sedation, tachycardia, and urinary retention. All TCAs are reported to cause these adverse effects in varying degrees of frequency and severity.1,2
The TCA agents listed on the right side of the slide are organized in descending order of adverse effects, starting with desipramine (fewest adverse effects), nortriptyline, imipramine, doxepin, and amitriptyline (most adverse effects).2,3
Because of the potential for adverse effects and adverse outcomes, amitriptyline should not be prescribed for people older than 65 years. Desipramine would be more appropriate for this population. Of all the drugs that are inappropriate for the elderly, amitriptyline is one of most frequently prescribed.4
Because the TCAs appear to be almost equally efficacious, a rational approach for clinical practice is to start with the agents with the fewest adverse effects, unless a specific “side effect,” such as nighttime sedation, is desired.
1. Rowbotham MC, Petersen KL, Davies PS, et al. Recent developments in the treatment of neuropathic pain. Proceedings of the 9th World Congress on Pain. Seattle, Wash: IASP Press; 2000:
2. Mackin GA. Medical and pharmacologic management of upper extremity neuropathic pain syndromes. J Hand Ther. 1997;10:
3. Tunali D, Jefferson JW, Greist JH. Depression and Antidepressants: A Guide. Madison, Wis: Information Centers, Madison Institute of Medicine; 1999.
4. Piecoro LT, Browning SR, Prince TS, et al. Database analysis of potentially inappropriate drug use in an elderly Medicaid population. Pharmacotherapy. 2000;20:
Most AEs

107. Caveats With the Antidepressants
Start at lowest dose available
Escalate slowly…every days
Slow weaning, over a week
Beware of drug interactions
Check for
Glaucoma
Prostatic obstruction
Heart block

108. Drug Interactions With Antidepressants
Coumadin
Alcohol ( cold medications)
Appetite suppressants
Quinolone antibiotics
Antihistamines
Tramadol
Anti epileptics
Bronchodilators

109. Neuroleptics Fluphenazine, methotrimeprazine For mild to moderate pain
Improve sleep
Similar analgesic effects to morphine without addictive properties or respiratory depression
Side effects
High sedative and anticholinergic effects
Extrapyramidal

110. Anticonvulsants Carbamazapine (Tegretol) Gabapentin (Neurontin)
Oxcarbezapine (Trileptal)
Topiramate ( Topramax)
Zonisamide ( Zonergan)
Levetiracetam( Keppra)
Lamotragine ( Lamictal)
Valproate ( Depakote)

111. Anticonvulsants Carbamazapine and valproate
for lancinating, burning pain. (neuropathic)
Neural invasion by cancerous tumor
Surgical scarring
Trigeminal neuralgia
For opioid induced myoclonus
dosing start at mg/d in cancer pain
Plasma levels need to be monitored

112. Anticonvulsants Carbamazapine and valproate Side effects Monitoring
Bone marrow suppression
Ataxia, diplopia, Nausea
lymphadenopathy, hepatic dysfunction
Monitoring
LFTs
CBC
Serum Drug levels

113. Gabapentin in Neuropathic Pain Disorders
FDA approved for postherpetic neuralgia
Neuropathic pain in patients who do not respond to CBZ and TCA.
Neuropathy, multiple sclerosis, migraine
Usually well tolerated; serious adverse effects rare
dizziness and sedation can occur
No significant drug interactions
Peak time: 2 to 3 h; elimination half-life: 5 to 7 h
Usual dosage range for neuropathic pain up to mg/d
Gabapentin is an anticonvulsant which has recently been approved for the treatment of postherpetic neuralgia, but it does not have FDA approval for this indication.1
Its mechanism of action has not been completely identified.
Gabapentin has limited intestinal absorption and is usually well tolerated. Among the more common adverse events associated with its use are dizziness and sedation. It has rare serious adverse effects.
No clinically significant drug-drug interactions are known.
The time to peak concentration is 2 to 3 hours, and the elimination half-life is 5 to 7 hours. Plasma clearance, however, decreases in elderly patients and in patients with impaired renal function.2
The effective dose for adjunctive therapy of partial seizures with or without secondary generalization in adults with epilepsy is 900 to 1,800 mg/day, given in divided doses tid and titrated over 3 days.2 For pain, clinical experience has shown that much higher doses are often necessary and well tolerated; the usual dosage range is up to 3,600 mg/day (tid-qid).1
1. Backonja M-M. Anticonvulsants (antineuropathics) for neuropathic pain syndromes. Clin J Pain. 2000;16:S67-S72.
2. Neurontin (gabapentin) [package insert]. Morris Plains, NJ: Parke-Davis; 1999.

114. Gabapentin Start as low as possible…..100 mgm q HS
Increase slowly by 100 mgm every three days
Caution regarding driving ( sedation)
Increase to 1200 mgm and assess pain relief
If > 50% relief, wait two weeks and reassess
Increase to maximum of 3600 mgm
Do not exceed 1200 mgm in elderly
Elixir in children mgm/kilo

115. Local anesthetics Lidocaine For neuropatheic pain
Short duration
Mexiletine longer acting
Doses same as antiarrhythmic dose
Side effects
Dizziness, lightheadedness, ataxia, N/V
High dose lead to tremor and convulsion
Lidocaine available as patches which have lower SE

116. Local anesthetics Ketamine At the N-methyl-D-aspartate (NMDA) receptor
Analgesic at subanesthetic doses
For neuropathetic pain
25 mg q 6 hrs , titrate by 25 mg q 24-48hrs
Side effects
Psychotomimetic, tachycardia, high BP , ↑ intracranial pressure

117. Benzodiazepines Diazepam, midazolam
Skeletal muscle relaxant and anxiolytic → ↑ pain threshold.
Side effects
Sedation, cognitive impairment, depression
Addictive
Serious withdrawal symptoms such as seizures

118. Corticosteroids Prednisone, Dexamethasone No ceiling effect
Opioid sparing effect
Dexamethasone
4-16 mg/d in divided doses
Oral or IV
Other non-analgesic effects
Relief of nausea and vomiting
Increase energy

119. Corticosteroids Indications Bone metastases Visceral pain
Neuropathic pain
Nerve compression from tumor
Soft tissue or musculoskeletal pain from inflammatory lesions
Headache from ↑ intracranial pressure
Pain from spinal cord compression

120. Bisphosphonates
Analgesic and prevents skeletal complications of malignancy
Treatment of hypercalcemia
Indications
Wide spread painful bone metastases at risk of complications
Multiple painful sites of disease at risk of hypercalcemia
Osteolytic bone disease where radiation is CI

121. Bisphosphonates
Pamidronate, zoledronic acid
given IV q 4 wks

122. Nonpharmacologic therapy
Surgery
Neuroablative blocks and neurolysis
Central and peripheral nervous system stimulation
Physical therapy