1. Pharmacologic Treatments of Pain
PMRC Nursing Module
Kim Chapman RN, MSc(N), CON(C)
Clinical Nurse Specialist, Oncology
October 2, 2009

2. Learning Objectives Understand the spectrum of pain pharmacology
Choose pharmacologic treatment options in chronic and cancer pain
Identify the more common side effects and strategies to manage those side effects

3. Mr. Pain’s Story
57 yr. old male diagnosed with small cell lung cancer. Has a lg. mass in his LUL along with mediastinal & (lt.) hilar adenopathy, extensive liver mets.
MI in takes ASA daily; peptic ulcer disease - takes losec daily
Active until about 1 mos. ago. Lost ~10 lbs. in the last 2-3 mos. Poor nutritional intake. Constipated. ++ ascites. Enlarged liver. Jaundiced.
Arrived for day 1 of his 1st chemotherapy (etoposide & cisplatin) with c/o abdominal pain.
Chemotherapy is for palliative intent.

4. Mechanistic Approach to Pain
Somatic
Superficial
NOCICEPTIVE PAIN
Deep
Visceral
MIXED
Central
Peripheral
Nociceptive Pain
Somatic:
superficial somatic - skin invasion or ulceration
deep somatic – bone, - muscle, soft tissue
Visceral:
organs
NEUROPATHIC PAIN
Others
Ashby MA et al :

5. Nociceptive: Somatic pain skin, muscle, connective tissue or bone
dull, sharp, aching, stabbing, throbbing, or pressure
well-localized
usually associated with tissue damage as well as inflammatory processes
eg. bone mets., pressure ulcer, infiltrated IV, incision
Nociceptive: Visceral pain
organs or tissue
gnawing, cramping, aching, sharp, colicky, dull, or sharp
localized or referred
eg. hepatomegaly, bladder spasms
Caused by direct stimulation of peripheral nociceptors

6. Neuropathic pain
nerve involvement centrally or peripherally
may arise as a direct consequence of a lesion or disease affecting the somatosensory system (IASP 2007)
sharp, tingling, burning, shooting, pins & needles, allodynia, burning, or lancinating

7. Pain Assessment Findings
P – Provocation & Palliation – lying, hiccups; certain positioning, heat, medication, relief of hiccups, relief of anxiety, sleep (BPI)
Q – Quality of Pain - Classic neuropathic pain both anterior thigh areas with the usual burning, stinging, & sharp pain along with allodynia - possibly due to femoral nerve obstruction or paraneoplastic syndrome. (LANSS). Dull, achy pain in abdominal area - nociceptive pain (BPI)
R – Region & Radiation - Pain moves from place to place; always persistent (BPI)
S – Severity (on a 0-10 scale) - Pain score of 8-9 at rest and 10 + with activity (ESAS & BPI)
T – Timing – constant unless using pain medication; time of day does not appear to influence pain experience (BPI)
Feldt Tool – used to assess pain in non-verbal patients
Reference
Feldt, K.S. (2000). Checklist of nonverbal pain indicators. Pain Management Nursing, 1(1),
Current medication – dosage/frequency, effects, side effects.
A list of prescribed and over the counter medications is valuable to determine what is working, what didn’t work, etc.
Ask about any alternative or complementary medications that the patient may have taken or may be taking.
BPI – Brief Pain Inventory; LANSS-
ESAS - Edmonton Symptom Assessment System

8. Key Patient Outcomes
Mr. Pain verbalizes that pain is reduced or relieved to his satisfaction.
Mr. Pain uses pharmacologic and non-pharmacologic interventions.
Mr. Pain participates in activities of daily living with appropriate medications.

9. What pharmacologic approach would you use?

10. Your Selection Opioids Non-Opioid Analgesics
Adjuvant Medications (Co-analgesics)

11. Pharmacological: Opioids
*Codeine
*Hydrocodone
**Tramadol
Morphine
Hydromorphone
Oxycodone
Methadone
Fentanyl
Sufentanyl
Levorphanol
Meperidine
Naloxone/Pentazocine
Meperidine (demerol)
Short duration
Low analgesic potency p.o.
High incidence of toxicity > 600mgs./24 hrs.
Naloxone/Pentazocine (talwin)
Limited oral bioavailability
Psychomimetic s.e. high
Never use with agonists
Weak Opioids
Opioids that can relieve mild to moderate pain, pain with a 4-6 score
Usually mixed with other medicines such as acetaminophen or aspirin.
Include hydrocodone, codeine, & tramadol.
Eg. of weak opioids mixed with acetaminophyen or aspirin include Tylenol® with codeine, Fiorinal® with codeine, & Phenaphen® with codeine.
Strong Opioids
Opioids that can relieve severe pain, pain with a score of greater than 7
Other examples include fentanyl, methadone, levorphanol, hydromorphone, & oxycodone.
Codeine combination products (>7 million prescriptions/yr)
Oxycodone combination products (>1 million prescriptions/yr)

12. Pharmacological: Non-Opioid
Adjuvant Medications
(Co-analgesics)
Anticonvulsants (carbamazepine,
phenytoin, gabapentin, pregabalin)
Antidepressants (amitriptyline, nortriptyline, desipramine)
NMDA blockers
Corticosteroids (dexamethasone)
Antispasmodic agents (baclofen)
Bisphosphonates (pamidronate, zoledronic acid)
Analgesics
Acetaminophen
NSAIDS (Anti-inflammatory medications)

13. So, Where’s the roadmap?

14. The Analgesic Stepped Approach
Increasing Pain
Severe Pain
Moderate
Pain
Fentanyl
Hydromorphone
Methadone
Morphine
Oxycodone
(+/- nonopioid)
(+/- adjuvants)
Mild
Pain
Codeine
Oxycodone
Tramadol
(+/- nonopioid)
(+/- adjuvants)
The WHO Analgesic Ladder (Available at: recommends escalation from the use of non-opioid therapies, to opioids selective for moderate pain, and when pain persists, opioids for severe pain. Adjuvants are recommended as required. This three-step approach to the management of pain aims to provide “the right drug in the right dose at the right time”. Surgical intervention may also be necessary to provide further pain relief.
Acetaminophen
ASA
NSAIDs/COXIBs
(+/- adjuvants)
World Health Organization. Cancer Pain Relief, with a Guide to Opioid
Availability. Geneva, Switzerland: WHO, 1996.
Leppert W, Luczak J. The role of tramadol in cancer pain management – a review.
Support Care Cancer 2005;13:5-17.

15. Mr. Pain’s Story GP started him on hydromorphone contin ↓ in pain
developed hives, urticaria & constipation

16. Opioid Therapy: Getting Started
Basic Considerations:
Patient opioid exposure &
experience
Patient fears (stigma)
Caregiver & physician attitudes, preferences & biases
Compliance
Convenience
Cost
Side effects
Pharmaco-clinical Considerations:
Patient sensitivities/allergies
Administration & absorption
limitations
Metabolism & clearance
Opioid profile
Factors that we need to consider when initiating opioid therapy
Patient exposure and experience-”I puked my guts out after they gave me morphine in the hospital after my surgery”
Administration/Absorption-g-tubes,short gut syndrome
Metabolism and Clearance-Renal dysfunction
Opioid Profile-Special properties. Methadone as Agonist and NMDA receptor antagonist
Fine PG. Journal of Pain, Aug. 2001

17. Hydromorphone: Key Points
~ 5 x more potent than morphine
Fewer drug interactions
May be used cautiously in renal failure
Very soluble - up to 300 mg/ml
Available in oral liquid, IR tablets, CR capsules, IR suppositories, & injectable form.
Less sedation, less pruritis, less constipation & vomiting than morphine
Available in oral liquid, IR tablets (2, 4, 8mg), CR capsules (3, 6, 12, 18, 24, & 30 mg), IR suppository, & injectable (1, 2, 4, 8mg/ml).
Dilaudid (Hydromorphone)
(Hydromorph Contin®)
Sustained Release
(Hydromorphone Injectable) Available 1, 2, 4, 8mg
Given Q4H
Available in 3mg suppository
Available 3, 6, 12, 24, 30mg
Given BID-TID
Available 2, 10, 50mg vials PO
SC butterfly
Hydromorphone PO or Injectable dosage may also be doubled at HS to avoid waking patient through the night.
CADD (Computerized Ambulatory Drug Delivery System) or Syringe Driver may be used to deliver a continuous dose of injectable Hydromorphone.
Hydromorphorone is approximately 5-6 times more potent than Morphine.
Sustained release opioids (Contin) should NOT be doubled at HS.

18. Pain & Substance Abuse Addiction Physical Dependence Tolerance
both physical & psychological components
continuous craving & need for effects other than originally intended
results in compulsive drug seeking behaviours
the 4 C’s: impaired control over drug use, compulsive use, craving, continued use despite harm (consequences)
Physical Dependence
pts. are physically acclimatized to the presence of the drug
occurs with long-term opioid use
pts will experience withdrawal if drug is withheld
if opiod withdrawn quickly then withdrawal
Predictable
Tolerance
Given dose that relieved pain no longer produces the same degree and duration of relief
JCAHO pain standards at
withdrawal: restlessness, tremors, rhinorrhea
No predictable pattern of occurrence. In many ways, poorly understood.
Risk of addiction is < 1% (Porter & Jick, 1980).
Physical dependence
results from continuous binding of exogenous opioids to opioid receptors.
“a state of adaptation that often includes tolerance & is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, &/or administration of an antagonist. It is not the same thing as addiction. The symptoms of withdrawal include hypertension, nausea, vomiting, fever, shivering, diarrhea, and muscle aches. These symptoms can be minimized by slowly decreasing the dose of opioids. Weaning should be planned for any patient who has been taking opioids for more than one week.”
(Taken from Accreditation Pain Standard: Making it Happen! Produced by The Canadian Pain Society)
Addiction
“is a primary, chronic, neurobiological disease, with genetic, psychosocial, and environmental factors influencing its development & manifestations. Characterized by the 4 C’s.”
Pseudoaddiction
“is a term which has been used to describe patient behaviours that may occur when pain is undertreated. Patients with unrelieved pain may become focused on obtaining medications, may “clock watch”, and may otherwise seem inappropriately “drug seeking.” Even such behaviours as illicit drug use and deception can occur in the patient’s efforts to obtain relief. Psuedoaddiction can be distinguished from true addiction in that the behaviors resolve when pain is effectively treated.”
(Victoria House, 1998; Wickham, 2001)

19. Screening for Addiction/Misuse Risk
Previous history of substance abuse/addiction
Family history of drug abuse &/or addiction
Previous “chemical coping” with life stresses
Significant psychiatric history
Previous high risk behaviours (esp. criminal activity)
High risk home environment

20. Which opioid(s) would you use with Mr. Pain?

21. Opioid Therapy: Which Approach?
Start with an IR opioid & titrate to effect When dose stable  CR opioid
fastest method for pain relief
Start with CR opioid & titrate dose q 1-3 days (or when side effects stable)
for stable, chronic pain
Start with CR opioid baseline dose & use IR opioid to titrate
once weekly (may be as soon as q2-4 days in patients with cancer), add the total daily dose of IR to the CR dose and repeat weekly until dose stable
These 3 methods are your preferred methods for chronic pain patients
If they add on an Oxy 10mg q12h = 1 Percocet q6h – which all MD’s prescribing percocet would do
So, why not start on a lower dose with the option of increasing the CR med??
May need to titrate more rapidly in cancer patient.

22. IR vs. CR Oral Opioids IR ORAL OPIOIDS CR ORAL OPIOIDS Onset of action
30 to 45 minutes
~ 2 hours
Oxycodone has 45 minute onset
Peak effect
60 minutes
- - -
Serum half-life
2 to 3 hours
Duration of action
4 hours
12 to 24 hours
Comments
Q6h dosing causes sub-therapeutic intervals
Monitor for end-of-dose failure
Note: These studies were conducted in healthy volunteers, or post-op

23. IR vs. CR Oral Opioids IR Oral Opioids CR Oral Opioids Advantages
Quick onset
Allows for quick titration (as early as every 24 hours)
Convenience and compliance
Uninterrupted sleep
Disadvantages
Frequent dosing
Interrupted sleep
Slower titration (48 to 72 hours)
Slower elimination in event of severe side effects

24. Mr. Pain’s Story
GP switched to an equianalgesic dose of morphine i.e. 100mg BID.
Uticaria disappeared. No change in hives or constipation.
c/o mild, infrequent nausea.
Started to become agitated & experienced hallucinations.

25. Opioid Rotation Changing one opioid to another
When: if pain is or has been relieved with original opioid, but toxicity limits further dose titration
Approximate dose ratio of two opioids required to produce a similar degree of analgesia
“equianalgesic tables”

26. Opioid Equianalgesic Doses
Oral
Parenteral
morphine
30 mg q3-4h around the clock OR 60mg q3-4h single or prn dosing
10 mg q3-4h
codeine
130 mg q3-4h
75 mg q3-4 h
hydromorphone
7.5 mg q3-4h
1.5 mg q3-4h
meperidine
300mg q 2-3h
100 mg q3h
oxycodone
30mg q 3-4h
N/A in Canada
Caution to docs switching from T3 to fentanyl to expect side effects such as sedation, in particular with patients that are opioid naïve
Note that 7-10% of patients may not metabolize codeine and thus would then be considered opioid naïve
There are many equianalgesic table…..they are guidelines
MEDICATION P.O. DOSE
Morphine 20 mg
Codeine mg
Oxycodone mg
Hydromorphone 3-4 mg
60-134mg oral morphine /day = 25 ug/hr td fentanyl1
Jovey R. et al. Managing Pain. p. 109
1 Health Cnada, 2009

27. Choose another opioid
Calculate the total dose of the analgesic over the past 24 hrs. If different routes have been used calculate separate totals.
Calculate equivalent dose of new opioid
Adjust starting dose of new opioid - consider ↓ initial dose by 25-50% if pain controlled by old opioid (no reduction if pain not controlled by old opioid) – accounts for incomplete cross-tolerance
÷ the dose by the # of administration x/day to obtain the interval dose
Calculate BTP pain medication dose.

28. Morphine “Natural” drug derived from opium poppy.
It’s the old standard NOT the gold standard.
Very effective orally (first pass through liver).
Duration of action for oral IR is ~ 4 hrs. & parenteral is ~ 3-4 hrs.
Active metabolites may accumulate in renal insufficiency leading to toxicity; not recommended in renal failure.
Fluctuating plasma levels can lead to variable efficacy & side effects. In the elderly bioavailability can be as low as 30%.
More sedating & GI s.e. than the semi-synthetic opioids.
More CNS effects in elderly (sedation, confusion, hallucinations)
•Histamine release (pruritis)
Injectable Available 10, 20, 30, 40mg scored tabs, Given Q1H PRN, BTP (breakthrough pain),
Suppository available in 10 & 20mg strengths
Available in 15, 30, 60, 100, 200mg tabs
Given BID/TID
Suppository available in 30, 60, 100, 200mg strengths
Ampules 10, 15, 50mg vials
Given Q4H, PO/elixir, PO/PR/gel caps
SC butterfly
Morphine dosage may be doubled at HS (up to an equivalency of 40 mg PO Morphine Q4H) in order to avoid waking patient at 0200.
CADD (Computerized Ambulatory Drug Delivery System) or Syringe Driver may be used to deliver a continuous dose of injectable Morphine.
IV Route of Administration is NOT recommended due to its short lived effect, and greater potential for toxicity.
Epimorphine is calculated and administered by anesthestist via pump for intractable pain in lower part of body (especially bilateral or midline pain).
Kadian
(Sustained Release) Available 20, 50, 100mg capsules.
Given q24h.
The patient’s pain should be stabilized on immediate release Morphine first.
The dose should be equivalent to the patient’s total 24hr Morphine dose.
Administer the initial dose of Kadian along with the last dose of immediate release Morphine.
Capsules may be opened and sprinkled on soft food~~not chewed or crushed.
Cannot be given rectally.

29. What next?

30. Codeine
10% of the overall population lacks the enzyme (CYP450 2D6) required to metabolize codeine to active drug morphine
2-5% of the population have relatively high amounts of the converting enzyme
Ceiling dose is 600 mg/day
Most constipating of all opioids
Some SSIs (Paxil, Prozac, Cymbalta) inhibit the conversion of codeine to morphine
IR: 15mg, 30mg, 60mg tablets
CR: 50, 100, 150, 200mg tablets

31. Oxycodone Hydrochloride
Strong semisynthetic opioid; potency 2x > morphine
Conversion to oxymorphone may be inhibited by drugs such as fluoxetine
CR form is OxyContin®.
Dose initiation: 10mg q12h for opioid naïve
No pharmacological dose ceiling for pure opioid agonists.
Can be used with close monitoring in renal failure
Sample titration schedule: 10, 20, 30, 40, 50, 60, 80, 100 mg q12h; can be titrated q24 hrs.
μ& κ-opioidreceptor agonist
Oxycodone Side Effects
shallow breathing, slow heartbeat
seizure (convulsions)
cold, clammy skin
confusion
severe weakness or dizziness
feeling light-headed, fainting
nausea, vomiting, constipation, loss of appetite
dizziness, headache, tired feeling
dry mouth, sweating, itching
IR: 5, 10, 15mg tablets
CR: 10, 20, 40, 80mg
Jovey, R. et al Managing Pain , Pg 96

32. Methadone Powder, capsule, liquid, suppositories
Long half-life (q8h). Half-life variable making it unpredictable with repeated doses  sudden severe toxicity.
Variable equianalgesic dose to other opioids
Individual titration with close monitoring is extremely important
Special authorization from Health Canada
Many drug interactions with CYP450 3A4
Less constipating; does not cause metabolite accumulation; less expensive
A good option in neuropathic pain
Methadone, a synthetic opioid has some unique properties. It is the only truly long-acting opioid available (others depend on a controlled release mechanism).
Methadone can be dosed once daily to prevent opioid withdrawal in opioid addicted people but is usually dosed q6-8h for pain. Extra caution is required when switching from another opioid to methadone due to a variable equianalgesic ratio. Naïve patients should be started on a small 5mg test dose before titrating. Use the “rules of 3” for safe titration: Never repeat a dose within 3 hours of a previous one, and never titrate the dose sooner than every 3 days. May cause ventricular arrhythmias (Torsades) in patients on higher doses who also have low Mg, K or Ca. It is metabolized by CYP450 3A4 enzyme. Many commonly prescribed drugs (Macrolides, Fluoroquinolones) may interfere with methadone metabolism and cause toxicity.
See slide #83 for web site of drug interactions

33. Cytochrome P450 Drug Interaction Table
University of Indiana
Department of Medicine
This is an excellent website, updated regularly, which lists all of the major Cytochrome P450 drug interactions. Most opioids are metabolized by 2D6. Fentanyl and methadone are metabolized by 3A4.

34. Fentanyl
Use if difficulty with oral meds; compliance issue; intractable side-effects
25ug. of Fentanyl range is mg oral morphine equivalents1
60mg of morphine or equivalent before switching to the 25ug. patch; 45mg if 12.5ug. patch.
When applying 1st patch continue with other pain medication x 24 hrs.
Rate of absorption can be affected by: fever, soap, oils, alcohol, shaving skin
Duragesic/Fentanyl Patch Available in 25,50,75,100 µg/hr
Applied q3days Topically on dry non hairy area back,
chest
upper arms When applying the initial patch the patient will require additional pain medication during the first 24 hours, as it is a slow released product.
To be used in combination with short acting narcotics, such asMorphine for breakthrough painShould not be used in conjunction with sustained released opioidsRate of absorption may be affected by:
·Fever
·Soap
·Oils
·Lotions
·Alcohol
·Shaving skin
If patch must be applied to a hairy area, clip hair with scissors do not shave. Apply patch and hold in place for 30 sec
If patch falls off and is not damaged may reapply firmly by applying micropore tape OR a new patch may be applied
Store at room temperature
When removing, fold sticky sides together and flush down toilet
Rotate patch sites
Duragesic patch: 12.5, 25, 50, 75, 100 ug.
1Health Canada, January 2009

35. Sufentanil (sufenta)
Approximately 5 to 10 times more potent than fentanyl
Relieves pain by stimulating opiate receptors in CNS25-50 mcg SL/buccal.
Good choice for use just before activity.
Pt. teaching re: taking it.
Possible side effects: respiratory changes, heart rhythm irregularity, peripheral vasodilation (blood pressure changes), inhibition of intestinal peristalsis (constipation), sphincter of Oddi spasm, & nausea/vomiting

36. Tylenol # 3 300mg acetaminophen + 30mg of codeine in each tablet
12 x Tylenol #3 (usual daily dose) = 3.6g total daily dose of acetaminophen & 360mg of codeine – this exceeds what is safely recommended for chronic use in healthy patients
Tylenol # 3 also contains caffeine.

37. Acetaminophen*- Suggested Dose Ceilings
4 gm/day > 10 days in healthy, well-nourished patients – short-term use in healthy patients
3.2 gm / day for chronic use in healthy patients
2.6 gm / day chronically in at risk patients
*Daily alcohol consumption, warfarin, fasting, a low protein diet, cardiac or renal disease increase the risk of hepatotoxicity
There is no actual published evidence for the commonly recommended dose ceiling of 4 gm / day of acetaminophen. Ken Latta, an academic pharmacist from Duke University has been collecting the literature on acetaminophen toxicity and has developed the above guidelines for the teaching hospitals affiliated with Duke.
The risk of hepatotoxicity increases with 3 or more drinks of alcohol per day. (U.S. FDA Jan, 2004)
Zimmerman & Maddry, 1995
Seeff et al., 1986
Swarm et al., 2001
Bromer MQ, Black M. Acetaminophen hepatotoxicity. Clin Liver Dis2003;7:351-67
Latta, 2000
Garcia Rodriguez, Arthritis Res 2001; Curhan 2002
Watkins et al., 2006.
Latta,

38. Tramadol
An opioid analgesic with a dual mechanism of action (weak affinity to the Mu receptor + inhibits the reuptake of serotonin & norepinephrine)
Recommended for the tx. of moderate - moderately severe pain.
CR tramadol can be initiated in opioid naïve at lowest dose
Less constipating then codeine
Maximum 400mg/day
Tramadol Side Effects
seizure (convulsions)
a red, blistering, peeling skin rash
shallow breathing, weak pulse
dizziness, drowsiness, weakness
nausea, vomiting, constipation, loss of appetite
blurred vision
flushing (redness, warmth, or tingly feeling)
sleep problems (insomnia)

39. Tramadol Dosing Immediate release (Tramacet)
One tablet is 37.5mg Tramadol HCL/ 325mg of acetaminophen
Maximum dose is 8 tablets per 24hours
Beneficial for acute pain
Extended release (Zytram XL1, Ralivia, Tridural)
Doses 100mg, 150mg, 200mg, 300mg, and 400mg
If on IR tramadol calculate 24 hr. dose & initiate total daily dose rounded down to nearest 100 mg, titrate up to max. of 400mg/day

40. What is the appropriate intervention for Pain’s opioid therapy?
Discontinue morphine and initiate tramadol.
Switch from MS Contin to OxyContin
Administer MS Contin once a day, rather than every 12 hours
Change dose of morphine and add a co-analgesic.
Answer: Switch from MS Contin to oxycontin
Tramadol
Immediate release (IR)
Start at 25mg./day, titrate slowly up to mg q4-6 hrs (max. 400mg/day)
Rapid analgesic onset: start at mg q4-6 hrs (max. 400mg/day)
Extended release
If not on IR tramadol start at 100mg/day; titrate up to max. 300mg/day
If on IR tramadol calculate 24 hr. dose & initiate total daily dose rounded down to nearest 100 mg, titrate up to max. of 300mg/day

41. Drug Selected: Oxycodone
Oxycontin 60mg (40mg & 20mg) BID
Oxy-IR 10mg q1hr. prn for BTP

42. Breakthrough Pain
Always have BTP ordered: ensure it is adjusted if regular dose is adjusted.
30-50% of regular dose q4hrs. (you may want to use 1/10 to 1/6 of the total daily dose usually q1hr.)
Same drug is usually used; may use other drugs.
>/= 3 doses BTP/24 hours add to regular dose
If pain is not improved after 1-2 BTP increments re-evaluate cause of pain.

43. Based on Mr. Pain’s description of his pain, would you consider a co-analgesic?

44. What co-analgesic would you add to Mr. Pain’s pain management plan?
Baclofen
Neurontin
Zoledronic acid
Nortiptyline

45. What was Prescribed? Neurontin (gabapentin) 100mg BID x 2 days
100mg TID x 2 days
200mg TID daily
Baclofen 5mg q8hr
Senokot-S 2 tabs. at hs

46. Which of the following side effects will you need to monitor when neurontin is initiated?
Constipation, nausea, itching, tremors, and hallucinations
Sedation, dizziness, nausea, confusion, and lower extremity edema
Ataxia, nausea, alterations in liver enzymes, and weight gain
Ataxia, nausea, vomiting, and diarrhea
Correct response: Sedation, dizziness, nausea, confusion, and lower extremity edema

47. Neurontin
Proven indications: postherpetic neuralgia (PHN) & diabetic neuropathy
Widely considered to be first-line (co-analgesic) agent for neuropathic pain despite off label status
Fewest drug interactions of all AEDs
Common adverse effects: somnolence, dizziness, fatigue, ataxia, S & S of CNS depression
References:
Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of pain neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 1998;280:
Rowbotham M, Harden N, Stacey B, et al. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 1998;280:

48. Neurontin
mg mg qhs; PHN initiate at 300mg day 1, 600mg day 2 in divided dose, 900mg day 3 in divided dose, & titrated further as needed up to mg
Supplied in 100mg, 300mg, 400mg, 600mg, 800mg capsules
Dose reduction needed in renal compromise
Morphine increases the neurontin concentration in the blood

49. What Other Co-analgesics are there?

50. Antiepileptic Drugs Neurontin Pregablin (lyrica) Lamotrigine
Well-tolerated with proven efficacy in neuropathic pain caused by neurotoxic anti-retroviral therapy in HIV-positive patients
Carbamazepine mg BID
Valproate 250mg daily to TID
Reason for analgesic efficacy unclear
Reduce membrane excitability
Suppress abnormal discharges in pathologically-altered neurons
Affects sodium channels
Indications: acute and chronic neuropathic pain from peripheral nerve syndromes
Trigeminal neuralgia
Diabetic neuropathy
Postherpetic neuralgia
Efficacy with both lancinating and burning pain
References:
Simpson DM, et al. Lamotrigine for HIV-associated painful sensory neuropathies: a placebo-controlled trial. Neurology 2003;60:
Eisenberg E, et al. Lamotrigine reduces painful diabetic neuropathy: a randomized, controlled study. Neurology 2001;57:

51. Pregablin (Lyrica) Indicated for the management of: Side Effects:
Neuropathic pain associated with diabetic peripheral neuropathy
Postherpetic neuralgia PHN)
Side Effects:
dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, constipation, euphoric mood, balance disorder, increased appetite, and thinking abnormal (primarily difficulty with concentration/attention)
References:
Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of pain neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 1998;280:
Rowbotham M, Harden N, Stacey B, et al. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 1998;280:

52. Pregablin (Lyrica) Available: 25mg, 50mg, 75mg,150mg, 300mg
Recommended dose/day: 150mg, 300mg, 600mg
PHN patients who tolerate LYRICA may benefit from up to 600 mg/day after 2 to 4 weeks of treatment with 300 mg/day
May take up to a week to receive benefit.
May exacerbate the effects of oxycodone, lorazepam, or ethanol on cognitive & gross motor functioning.
Discontinue gradually over a minimum of 1 week.

53. Cyclic Antidepressants
Amitriptyline
Best-established efficacy; most widely used for pain
Highest anticholinergic s.e. profile of all cyclic antidepressants
Common s.e.: sedation, constipation, dry mouth, blurred vision, urinary retention
10-25mg mg qhs
Nortriptyline
Less sedation & anticholinergic side effects than amitriptyline
Common adverse effects include sedation, dry mouth, constipation
10-25mg qhs
Desipramine
Tolerability & efficacy similar to that of nortriptyline
Less anticholinergic side effects than amitriptyline
25mg qhs
Avoid cyclic antidepressants if QTc > 440 msec or if AV block

54. Non-Opioid Analgesics: Acetaminophen
Used for mild-moderate nociceptive pain
Dose ceiling
2 key side effects: renal toxicity & risk for hepatotoxicity
Usual dose: 325mg 1-2 tabs q4-6h
Acetaminophen is thought to act on the recently discovered COX-3 enzyme. It has been used over the counter for decades for the treatment of mild to moderate nociceptive pain. There is evidence for effectiveness in post operative pain. The maximum recommended daily dosage of acetaminophen is 4000 mg. Dosages in excess of 4000 mg per day risk hepatotoxicity by exceeding the ability of the liver to glucuronidate toxic metabolites. It is recommended that the daily dosage of acetaminophen be reduced to less than 3000 mg per day in patients with hepatic diseases such as hepatitis and cirrhosis.
There is no actual published evidence for the commonly recommended dose ceiling of 4 gm / day of acetaminophen. Ken Latta, an academic pharmacist from Duke University has been collecting the literature on acetaminophen toxicity and has developed the above guidelines for the teaching hospitals affiliated with Duke.
The risk of hepatotoxicity increases with 3 or more drinks of alcohol per day. (U.S. FDA Jan, 2004)
-Evidence in postop pain: A single dose of 1000 mg had an NNT of 3.8 ( ) for at least 50% pain relief over 4-6 hours in patients with moderate or severe pain (a single dose of mg had an NNT of 4.6)
Case, 2003; Zimmerman, 1995, 2000; Bromer, 2003; Perneger, 1994; Garcia Rodriguez, 2001; FDA Sept. 2002; Health Canada Feb. 2003; Curhan

55. NSAIDS # & diversity have increased over the past 20 yrs.
Evidence detailing effectiveness is contradictory – COX I & COX II
Analgesic & anti-inflammatory effects
Routes: Oral preferred, IV faster onset
Ceiling Dose
Monotherapy for mild-moderate pain
Co-analgesic for severe pain
Effective in inflammatory arthritis
Little long-term evidence in osteoarthritis
Functions of prostaglandins:
Protect gastric mucosa
Support renal and platelet function
Inflammation & pain response
Pros and Cons of NSAIDs
Optimal analgesia may require COX I and COX II1
Increased risk of CV events with COXIBs2, 3,4
COXIBs block prostacyclen but not thromboxane5
COXIBs have no antiplatelet activity and do not substitute for ASA
Delayed healing of fractures in animals6
1. McCormack, 2002; 2. Mukheriee D. Jama 2001; 3. Howard PA, Jam Coll Cardiol, 2004;
4. Topol E, NEJM Marcus A.J. NEJM 2002; 6. Simon AM. JBMR 2002
Action: Both traditional COX-1 & -2 & selective COX-2 inhibit prostaglandin synthesis at peripheral sites of inflammation; central effect poorly understood
Ibuprofen 400mg NNT of 2.4 ( )
ASA 650 mg: NNT pf 4.4 ( )
Diclofenac 50mg: NNT of 2.3 ( )
Naproxen 550mg: NNT of 2.6( )
NNT of at least 50% pain relief over 4-6hrs following single dose.
Non-steroidal anti-inflammatory drugs can be very effective in the management of nociceptive pain association with tissue damage (including surgical pain) as well as inflammation.
Reference for Ibuprofen: Barden J, Edwards JE, Collins SL, McQuay HJ, Moore RA. Single dose ibuprofen for postoperative pain. The Cochrane Library, Update Software, Oxford, 2002.
Reference for ASA: Edwards JE, Oldman A, Smith L, Collins SL, Carroll D, Wiffen P, McQuay HJ, Moore RA. Single dose Aspirin in acute pain. The Cochrane Library, Update Software, Oxford, 2000 (updated with no additional results 2002).
Reference for diclofenac: Barden J, Edwards JE, Collins SL, McQuay HJ, Moore RA. Single dose diclofenac for postoperative pain. The Cochrane Library, Update Software, Oxford, 2002.
Reference for naproxen: Mason L, Edwards, JE, Moore RA, McQuay HJ. Single dose naproxen for acute postoperative pain: a quantitative systematic review. BMC Anesthesiology 2003;3:4
A systematic review found that in most cases, the oral route of administration provides equivalent analgesia with fewer adverse effects compared to rectal and parenteral routes. Reference: Tramer M, Williams J, Carroll D, Wiffen PH, McQuay HJ, and Moore RA. Comparing analgesic efficacy of non-steroidal anti-inflammatory drugs given by different routes for acute and chronic pain. Acta Anaestheiologica Scandinavica 1998;42:71-79.

56. NSAIDs/COXIBs
Increase risk of exacerbation of underlying renal insufficiency
Increase risk of fluid retention
Increase risk of cardiovascular complications
Increase risk of GI bleeds (especially NSAIDs in patients requiring concomitant ASA for cardiovascular prophylaxis)

57. NSAIDs Side effects Contraindications GI distress
Bleeding 2° to platelet dysfunction
Renal failure
Bronchoconstriction
? Delay in bone healing

58. Which one?
Ketoprofen (Orudis) – mg daily (RA & OA); 50mg TID-QID (menstrual cramps & mild-to-moderate pain)
Indomethacin (Indocid) – 25mg BID - TID
Ibuprofen (Motrin) – mg TID
Toradol (Ketorolac) – 10mg q4-6hr
Naproxen (Naprosyn) – mg BID
Diclofenac (Voltaren) – 25-50mg TID or 75mg SR daily (maximum dose 150mg)
ASA – mg QID/q4hr
Rofecoxib (Vioxx) - Sept removed from market
Celecoxib (Celebrex) – mgQD-BID
The problem with ASA must be underscored. In both the CLASS and VIGOR trials, concomitant use of ASA (as much as 325 mg per day) negates the GI protective effects of COXIBs. Given the widespread use of low-dose ASA, one has to wonder just how much safety benefit patients who use COXIBs actually obtain. For a good discussion on the subject, see: *McQuay HJ, Moore RA. Side effects of COX-2 inhibitors and other NSAIDs. In Proceedings of the 10th World Congress on Pain, Jonathon O. Dostrovsky, Daniel B. Carr, Martin Koltzenburg Eds. Progress in Pain Research and Management Volume 24, pp , IASP Press, Seattle.
**Chan FKL, Hung LCT, Suen BY, et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med 2002;347:
Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ 2000;321:
COXIBs = NSAIDs
10-17% of patients have increased BP1
Acute and chronic renal toxicity2
Double the risk of hospitalization for CHF3
Delayed gestation
Increased miscarriage risk4
No evidence in neuropathic pain
1. Cheng HF. Hypertension, 2004; 2. DeMaria AN. JPSM 2003; 3. Garcia-Rodriguez LA. Epidemiology 2003; 4. Li DK. BMJ 2003
*McQuay HJ, Moore RA.. In Proceedings of the 10th World Congress on Pain.
Jonathon O. et al. Progress in Pain Research and Management Volume 24, pp , IASP Press, Seattle.
**Chan FKL, et al. N Engl J Med 2002;347:
*Taking ASA nullifies the GI protective effect of COXIBs

59. Toradol Suggested for moderate pain.
Recommended as an alternative to low-dose opioids.
Suggested to limit oral use x 7 days or parenteral to 2 days.
Major s.e. are GI; need something for GI side-effect prevention.

60. Cytoprotective Agents
Sucralfate (1gm Qid)
misoprostol (200ug Qid) * not best choice
H2 receptor antagonists eg. Cimetidine, ranitidine
Omperazole 20-40mg/day

61. Is an NSAID a good choice for Mr. Pain?
History of ulcer complications
Multiple NSAIDS
High-dose NSAIDS
Concomitant anticoagulant use
Age >/= 60yrs.
Concomitant corticosteroid use
History of cardiovascular disease

62. Other Medications for Pain
Muscle relaxants
Cyclobenzaprine, Baclofen
Local anesthetic congeners
IV Lidocaine, oral Mexiletine
NMDA (N-methyl D-aspartate) blockers
Dextromethorphine, ketamine
Alpha-2 agonists
Clonidine, Tizanidine
Botulinum Toxin
Van Tulder MW, Touray T, Furlan AD, Solway S, Bouter LM. Muscle relaxants for nonspecific low back pain: a systematic review within the framework of the cochrane collaboration.
Spine Sep 1;28(17): Mao J, Chen LL. Systemic lidocaine for neuropathic pain relief. Pain Jul;87(1):7-17. Kalso E, Tramer MR, McQuay HJ, Moore RA. Systemic local-anaesthetic-type drugs in chronic pain: a systematic review. Eur J Pain Mar;2(1): Smith HS, Barton AE. Tizanidine in the management of spasticity and musculoskeletal complaints in the palliative care population. Am J Hosp Palliat Care Jan-Feb;17(1):50-8. Review. Lang A.M. Botulinum toxin type A therapy in chronic pain disorders. Arch Phys Med Rehabil Mar;84(3 Suppl 1):S69-73; quiz S74-5. Review.

63. Mr. Pain has already experienced uticaria, rash, constipation, agitation, & hallucinations from his opioid therapy. What other side effects might you anticipate with ongoing opioid therapy?
Discuss the acute side effects with patients before prescribing. They are more likely to persist if they know that the acute side effects are temporary.
Be proactive with side effects

64. Side Effects of Opioids
COMMON
LESS COMMON
RARE
Side effect
Nausea and vomiting
Constipation
Sedation and drowsiness
Confusion
Myoclonus
Dry mouth
Urinary retention
Sweats
GE reflux
Pruritus
Respiratory depression (very rare in properly titrated patients)
Note: Long term side effects of chronic use covered in later section.
Respiratory depression issue in opioid naïve patients given improper doses, i.e. medication errors. Case of girl at Sick Kids in Toronto receiving 10 mg IV instead of 1 mg IV precipitating respiratory arrest and death.

65. Treatment of Common Opioid Side Effects
Nausea and vomiting
Ondansetron 8mg q8hr prn
Haloperidol mg od-tid
Phenothiazine 5-10 mg PO q4-6h prn
Dimenhydrinate often too sedating
If motility is an issue
Metoclopramide mg qid
Constipation
Use dietary measures first (bran, flax, prunes)
Osmotics-MOM, lactulose
Stool softeners - docusate
Stimulants-senna, bisacodyl
Suppositories-dulcolax
Enemas
Constipation-highlight differences in management between cancer and non-cancer population (ie more aggressive use of bowel stimulants in cancer patients)
Lack evidence to support the use of docusate in relieving constipation
See reference section for treatment of side effects document
Discuss pros and cons of each antiemetic. Use drugs of choice from your practice

66. Opioid Neurotoxicity
Presents as agitation, confusion, myoclonus, hallucinations & rarely seizures
Possible precipitants
Infection/Sepsis
Dehydration
Decreased renal clearance
Rapid dose escalation
Management: ↓ dose or hold medication until sensorium clears, Opioid rotation, Consider hydration with both options

67. Mr. Pain’s Story
Presented for his 2nd chemotherapy tx. with well controlled pain.
Reported taking fewer BTP medication, once or twice q3-4 days.
Oncologist decreased his pain medication.
At this point you need to determine what is happening…..time to reassess, readdress
Determine what is happening, treat the underlying disease.
It is a common occurrence that patients spontaneously discontinue their own meds-sometimes up to 1/3 of them
Decreasing Dose or Discontinuing Opioids
Possible Indications
Dramatic decrease in pain
Increase in side effects despite stable dosage
Resolution of underlying problem
Active addiction
If patient wants to discontinue

68. Opioid Dose Reduction
Careful reduction to decrease opioid toxicity – monitor pain control
Dose reduction may include the concurrent addition of adjuvant analgesics
Tapering Schedule
First 48 hours: decrease daily dose of opioid by 50% in
Second 48 hours: *decrease daily dose by 25% (assuming no increase in pain)
Third 48 hours: *decrease daily dose by 25%
May prescribe IR opioids to minimize interdose pain or withdrawal symptoms
Remember this is a non fatal withdrawal
In tools section there is a two page document title “managing opioid withdrawal” that can be utilized…….this is an alternate and slower method than the one mentioned above.
10% reduction per day, per week, per month, etc.
Slow dose reduction at the end of the wean.
Use Clonidine for withdrawal symptoms.
Use Clonazepam for withdrawal symptoms.
Methadone withdrawal symptoms may persist after end of withdrawal.

69. Putting it Altogether
Susan has been receiving hydromorphone 2 mg s/c. She is now able to tolerate oral medication. The best option for the oral dose would be:
A. 1 mg
B. 2 mg
C. 4 mg
D. 8 mg

70. Putting it Altogether A. 15 mg BID B. 30 mg BID C. 45 mg BID
Jane has been taking 10 mg. of morphine by mouth q4hr with good relief. A decision has been made to switch her to a sustained release morphine. The starting dose should be:
A. 15 mg BID
B. 30 mg BID
C. 45 mg BID
D. 60 mg BID

71. Take Home Pearls Assessment is key.
Goal is to reduce pain to an acceptable level.
Involve the patient in goal setting & negotiating analgesic strategies.
Do not delay treating pain – avoid chronic pain.
A multi-modal approach is recommended (pharm & non-pharm).
Prevention is better than treatment – give meds regularly.
Use least invasive route possible & avoid IM injections.
Anticipate & manage side effects
If there is a question with regard to “no ceiling dose” how would you respond?
no pharmacological ceiling dose
Limitations may be based on side effects
The key is to document well the need/outcome of a high dose
consider dosing as dynamic not static
** If the MD has a “personal” dose ceiling that the patient has reached and the patient remains less than well controlled, this may be an indication for a consult**

72. THANK YOU