1. Non-Opioid Pharmacologic Options
Chris Greer, BPharm.
St. Luke’s Rehabilitation Institute

2. Learning Objectives
The participant will understand the mechanism of action of selected non-opioid medications for the treatment of pain.
The participant will know needed renal dose adjustments of selected non-opioid medications for the treatment of pain.
The participant will know significant cautions for the use of selected non-opioid medications for the treatment of pain.

3. Audience Participation
Menti.com

5. SPACE Trial Randomized pragmatic clinic trial
240 patients with severe chronic back or hip or knee osteoarthritis pain
Recruited from Veterans Administration outpatient clinics
Treatment arms:
Opioid therapy
Non-opioid therapy
Outcome Measures: BPI interference and BPI severity scales

6. Space Trial Opioid Arm Immediate release:
morphine
hydrocodone/acetaminophen
oxycodone
Dose titrated every 4 weeks to a max of 100 morphine equivalent dose. (MED)
Rotation to another agent if no clear response at 60 MED.
Long acting agents added to simplify regimen

7. Space Trial Non-opioid arm
Step one agents
Acetaminophen
Non-steroidal anti-inflammatory medications
Step two agents
Nortriptyline
Amitriptyline
Gabapentin
Topical agents
Capsaicin
Lidocaine

8. Space Trial Non-opioid arm
Step three agents
Pregabalin
Duloxetine
Tramadol (which at the time of the start of the trial was not a controlled substance)

9. Acetaminophen Inhibits the formation of prostaglandins
Inhibits COX1 and COX2 and may be COX2 selective.
Active with low levels of arachidonic acid and peroxides
Relatively inactive at higher levels so lacks the obvious anti-inflammatory effect of NSAIDS.
First line agent due to excellent tolerability
Used as an additional ingredient in multiple combination products.

10. Acetaminophen Adult dosage forms: Acetaminophen 325 mg tab
2 tablets every 4-6 hours
Acetaminophen 500 mg tab
2 tablets every 6 hours
Acetaminophen 650 mg extended release
2 tablets every 8 hours
Kinetics: half-life 2-3 hours over 4 with hepatic injury
Renal dose: CrCl 10-50: give q6h; CrCl <10: give q8h;
HD/PD: no supplement

11. Acetaminophen Cautions / side effects:
Allergic reactions / hypersensitivity / rash
Renal tubular necrosis / actute kidney injury
Renal impairment in long term use
Hepatotoxicity

12. Acetaminophen Hepatoxicity: Can occur at acute and chronic over doses.
Max of 4,000 mg per day
Acute dose of 4 gm – 10 gm within 8 hours toxic
N-acetyl-p-benzoquinone imine (NAPQI) is the toxic metabolite that develops as CYP 450 enzyme metabolizes acetaminophen when glucuronidation and sulfation is saturated.

13. Acetaminophen Hepatoxicity – Increased risk with: Alcohol use
Prolonged fasting
Malnutrition
Drugs that can induce CYP 450 enzymes like carbamazepine, primidone, rifampin, efavirenz, and St. John’s wort may increase risk

14. Acetaminophen Uses Fever, body aches and sore throat from cold/flu
Headache
Osteoarthritis
Recent Cochrane review found that acetaminophen is only minimally effective for hip and knee osteoarthritis.

15. Arachidonic acid cyclooxygenase prostaglandin (PG) H2 PGE2 thromboxane (Tx) A2 prostacyclin (PGI2) PGD2 PGF2α

16. COX 1 vs COX 2 COX 1 found throughout tissues – many functions
Prostaglandins
Platelet aggregation
GI mucosal protection and repair
Renal cortical blood flow
COX2 inducible with injury and inflammation
Kidney medullary blood flow

17. Non Steroidal Anti-Inflammatory Medications (NSAIDS)
Earlier practice was to classify NSAIDS into respective chemical classes.
With the development of COX2 selective agents the NSAID class fell into either non-selective and selective agents.
Now agents can be grouped into a single class of non-aspirin agents

18. NSAIDS
Common NSAIDS by COX2 selectivity Aspirin very low Naproxen low Ibuprofen low Meloxicam medium Diclofenac medium Celecoxib high

19. Naproxen Dose: Kinetics: hepatic metabolism half life 12-17 hours
OTC: 220 mg Q12
RX: mg Q12
Kinetics: hepatic metabolism
half life hours
Renal Dosing: Avoid use for CrCl < 30
Hepatic impairment: caution advised

20. Ibuprofen Dose: Kinetics: hepatic metabolism half life 1.8-2 hours
OTC: mg Q4-6 hrs max 0f 1200 mg/day
RX: Rheumatoid and Osteo arthritis mg
tid-qid max of 3200 mg/day
Other indications mg
q4-6hrs max of 2400 mg/day
Kinetics: hepatic metabolism
half life hours
Renal Dosing: caution advised
Hepatic impairment: caution advised

21. Meloxicam Dose: Kinetics: hepatic metabolism half life 15-20 hours
mg daily
Kinetics: hepatic metabolism
half life hours
Renal Dosing: mild to moderate no adjustment
CrCl < 15 avoid use
Hepatic impairment: No adjustment or Child-Pugh class A or B, recommendation for Child-Pugh
Class C not defined.

22. Diclofenac Dose: sodium salt form Kinetics: hepatic metabolism
50 mg TID- QID
75 mg BID
Extended release 100 mg daily to BID
Kinetics: hepatic metabolism
half life 1.9 hours
Renal Dosing: advanced renal disease avoid use
Hepatic impairment: decrease dose

23. Diclofenac Topical
Dose: Lower extremity: 4gm QID max 16 gm per joint per day; 32gm per day total Upper extremity: 2gm QID max 8 gm per joint per day; 16gm per day total Topical administration absorption: When compared to oral dose of 150 per day 4gm qid = 0.6% of Cmax and 5.8% AUC 12 gm qid= 2.2% of Cmax and 19.7% AUC

24. Celecoxib
Dose: mg BID Kinetics: hepatic metabolism half life 11.2 hours Renal Dosing: Severe impairment avoid use Hepatic impairment: Child-Pugh class B: decrease dose 50% Child-Puch class C: avoid use

25. NSAID Cautions Risk of GI Ulceration, Bleeding, and Perforation
Celecoxib package insert

26. NSAID Cautions Risk increased cardiovascular events
COX 2 selectivity: Platelet COX1 production of vasoconstrictive thromboxane A2 is unopposed by reduced production of vasodilatory prostacyclin and PGE2
NSAIDs may cause increased salt and water retention increasing blood pressure and risk of heart failure.
Low dose naproxen was thought to have the lowest CV risk of the non aspirin NSAIDs. Precision Trial showed that moderate dose celecoxib has similar CV risk to Ibuprofen and Naproxen

27. NSAID Cautions Managing risk:
Use the lowest effective dose and avoid long term use if possible
If high GI risk consider COX2 selective + PPI
Concomitant Aspirin + COX2 selective NSAID loses GI advantage but may be better due to less interference with aspirin effect.
Regulatory History of the Interaction Between Aspirin and Other Nonprescription NSAIDs April 24, 2016 Jenny Kelty, MD Medical Officer Division of Nonprescription Drug Products Office of Drug Evaluation IV CDER, FDA

28. NSAID Cautions
Ibuprofen and Naproxen can interfere with aspirin activity if the cox binding site is occupied and the aspirin can not irreversibly bind.
One suggested approach is to give the non enteric coated aspirin 30 minutes prior to or 8 hours after the NSAID. Enteric coated 2-4 hours prior to NSAID.
This is problematic with round the clock dosing.
Regulatory History of the Interaction Between Aspirin and Other Nonprescription NSAIDs April 24, 2016 Jenny Kelty, MD Medical Officer Division of Nonprescription Drug Products Office of Drug Evaluation IV CDER, FDA

29. Quiz Time
Kahoot!

30. Other Agents
Amitriptyline and Nortriptyline Duloxetine Gabapentin and Pregabalin Topical Lidocaine Topical Capsaicin

31. Antidepressants Amitriptyline and Nortriptyline – TCA Duloxetine SNRI
Inhibit norepinephrine and serotonin reuptake
Used for neuropathic pain
Pain modulation may occur through adrenergic activity at the supraspinal, the dorsal horn spinal cord and dorsal ganglia level.
Opioid system plays a role

32. Amitriptyline Dose: 25-100 mg QHS
Start at 25 mg and titrate slowly. Max of 150 mg
Kinetics: hepatic metabolism
half life hours
metabolized to nortriptyline hours
Renal Dosing: no adjustment
Hepatic impairment: caution advised

33. Nortriptyline Dose: 25-150 mg QHS
Start at 25 mg and titrate slowly. Max of 150 mg
Kinetics: hepatic metabolism
half life hours
Renal Dosing: no adjustment
Hepatic impairment: caution advised

34. Amitriptyline & Nortriptyline
Cautions:
Anticholinergic effects greater with amitriptyline
QT interval warning with amitriptyline
Caution in elderly
Suicide risk in patients < 25 yo
Seizure history
Glaucoma

35. Duloxetine Dose: 60 mg daily Start at 30 mg x 1 week then 60mg daily
Kinetics: hepatic metabolism
half life 12 hours
Renal Dosing: avoid use for CrCl < 30
Hepatic impairment: avoid use

36. Duloxetine Cautions: Suicide risk in patients < 25 yo
Seizure history
Glaucoma
Hypertension
Mania / Hypomania
Avoid abrupt withdrawal

37. Gabapentin & Pregabalin
Anticonvulsants that block voltage dependent CA++ channels
Modulates excitatory neurotransmitter release
Do not bind gaba receptors
Used for neuropathic pain

38. Gabapentin Dose: 300-1200 mg TID
Start at 300 mg and titrate slowly. Max of 3600 mg
Kinetics: excreted in urine
half life 5-7 hours
Renal Dosing: CrCl mg BID
CrCl mg Daily
CrCl < mg HD = supplemental dose
Hepatic impairment: no adjustment

39. Pregabalin Dose: 75-300 mg BID
Start at mg BID and titrate slowly. Max of 600 mg
Kinetics: excreted in urine
half life 5-7 hours
Renal Dosing: CrCl mg /day given BID
CrCl mg /day given BID
CrCl < mg Daily
HD = supplemental dose
Hepatic impairment: no adjustment

40. Gabapentin & Pregabalin
Cautions:
Somnolence
Depression / suicidality
Avoid abrupt withdrawal
Peripheral edema
Angioedema
Rhabdomyolysis

41. Capsaicin Topical agent –Hot pepper
Binds nerve membrane receptors to desensitize nociceptive neurons through depletion of substance P. May decrease pain transmission to CNS.
Dose:
0.025%-0.075% TID to QID
Cautions:
Do not apply to broken skin.
Burning, erythema and thermal hyperalgesia

42. Lidocaine Topical agent –local anesthetic - 5% patch, 4% patch
Inhibits sodium ion channels. Amide local anesthetic
Dose:
Max 3 patches at a time applied to painful areas for 12 hours per day
Kinetics: hepatic metabolism
half life hours
Renal Dosing: smaller treatment areas recommended
Hepatic impairment: caution advised

43. Quiz Time
Kahoot!

44. SPACE Trial Results
Analgesic months = AM
Opioid Arm
Non-Opioid Arm
Number of study drugs:
1.7
3.8
AM - Acetaminophen
0.1
2.6
AM - oral NSAID
0.4
5.9
AM – topical
3.5
AM- Tramadol
AM – Opioid
8.1

45. Quiz Time
Kahoot!

46. BPI interference scale
SPACE Trial Results
Opioid Arm
Non-Opioid Arm
BPI interference scale
baseline
5.4
5.5
12 months
3.4
3.3
BPI severity scale
6 months
4.1
4.0
3.5

47. Contact Chris Greer at greerc@st-lukes.org
Thank You!
Questions or Comments?
Contact Chris Greer at