1. Pain Management & Opioid Analgesics

2. Objectives Determine proper opioid dosing
Differentiate between specific opioid analgesics and be able to convert between agents
Discuss basal and bolus doses for PCA
Discuss adverse reactions of opioids
Review the Sole Provider program
Discuss how to properly write a prescription for a controlled substance

3. Pain
Definition
An unpleasant sensory & emotional experience associated with actual or potential tissue damage or described in terms of such damage
Types
Nociceptive
Somatic – bone pain, skin, soft tissue trauma
Visceral – ab pain due to tumor invasion
Neuropathic – post herpetic neuralgia, post-mastectomy, phantom limb

4. Choosing Analgesic Therapy
What type of pain?
Nociceptive vs. neuropathic
Acute vs. chronic
Mild vs. severe
What route should be used?
What agent should be used?
Type, severity of pain
Pt characteristics – side effects, elderly, allergy, co-morbid conditions, tolerance, previous narcotics used
Insurance, cost

5. WHO Ladder of Analgesics
WHO has developed a three-step "ladder" for cancer pain relief.
If pain occurs, there should be prompt oral administration of drugs in the following order: nonopioids (aspirin and paracetamol); then, as necessary, mild opioids (codeine); then strong opioids such as morphine, until the patient is free of pain. To calm fears and anxiety, additional drugs – “adjuvants” – should be used.  To maintain freedom from pain, drugs should be given “by the clock”, that is every 3-6 hours, rather than “on demand” This three-step approach of administering the right drug in the right dose at the right time is inexpensive and 80-90% effective. Surgical intervention on appropriate nerves may provide further pain relief if drugs are not wholly effective.
**To maintain freedom from pain, drugs should be given “by the clock”, that is every 3-6 hours – to keep ahead of the pain**

6. Non-opioid analgesics
Aspirin
NSAIDs
Acetaminophen
Adjuvants
Antidepressants – amitriptyline, duloxetine
Anticonvulsants – carbamazepine, gabapentin, pregabalin
Anesthetics – lidocaine patch (12 hours on, 12 hours off)
APAP – max dose of 4 g/d but may change to 3g/d
Lidoderm patch – can be cut to area & can apply up to 3 patches in a single application – in place for 12 hours, then 12 hours off
Contains metal – remove prior to MRI

7. Potency of Opioids Weak Agonists Strong Agonists
Propoxyphene (Darvon, Darvocet)
Codeine
Hydrocodone/APAP (Vicodin, Lortab, Lorcet, Norco)
Tramadol
Morphine
Oxycodone
Hydromorphone (Dilaudid)
Fentanyl (Duragesic, Sublimaze)
Methadone (Dolophine)
Meperidine (Demerol)
Propoxyphene – limited analgesic effect**may be withdrawn from the market in the future by FDA due to increasing incidence of cardiotoxicity in the elderly, deaths due to overdose (accidental and intentional), overprescribed in the elderly
Codeine – metabolized to morphine in the liver via CYP2D6 (O-methylation) with morphine conc about 10% (other metabolism via N-demethylation to nor-codeine) – has more side effects than morphine
Hydrocodone – always combined with APAP or ibuprofen – which limits its dosing

8. Tramadol Synthetic analog of codeine but is NOT controlled
Weak agonist/low affinity at mu receptor and also weak SNRI (which inhibits pain transmission in the spinal cord)
Use with caution in pt on TCAs, MAOIs, SSRIs as it may lower seizure threshold
Max dose is 400 mg/day but 300 mg/day if >75yo; renal dosing if CrCl<30
Tramadol is 5-10 times less potent than morphine and reported to cause less respiratory depression
Approximately 50 mg tramadol = 60 mg codeine
Since it is a weak agonist, it is partially antagonized by naloxone
Tramadol – unique molecule: synthetic analog of codeine but is NOT controlled; weak agonist/low affinity at mu receptor; ** approximately 50 mg tramadol = 60 mg codeine**partially antagonized by naloxone**also weak SNRI (which inhibits pain transmission in the spinal cord) use with caution in pt on TCAs, MAOIs, SSRIs as it may lower seizure threshold
Max dose is 8 tabs/d but 6 tabs/d if >75yo; renal dosing if CrCl<30
Tramadol is 5-10 times less potent than morphine and reported to cause less respiratory depression

9. Considerations in choosing opioids
Renal impairment
Preferred oral agent: hydromorphone
Use with caution: morphine, codeine
Avoid meperidine
Metabolites can accumulate and cause seizures
Other cautions with meperidine
Avoid in pts with CHF, hepatic insufficiency, elderly
Avoid use in pts on MAOIs (phenelzine, selegeline, linezolid) in past 14 days
Avoid with MAOis d/t serotonin syndrome

10. Duration of analgesic effect
Opioid
Half-life
Onset
Duration of analgesic effect
Fentanyl
IV: 2 – 4h
Patch: 17h
IV: within minutes
Patch: 12-24h
IV: 0.5 – 1h
Patch: 72h
Hydromorphone (Dilaudid)
2 – 3h
IV: min
PO: 30 min
3 – 5h
Methadone**
8 – 59h
30 – 60 min
4 – 8h
Morphine
2 – 4h
IV: min
PO (IR): min
IR: 3 – 6h
SR: 8 – 12h
Meperidine (Demerol)
3 - 5h
(15-30h for metabolite)
10 – 45 min
Codeine
3 – 4h
4 – 6h
Oxycodone
IR: 2 – 5h
SR: 5h
15 – 60 min
SR: 12h
Hydrocodone
10 – 60 min
Table compares some of the PKS
All have similar t1/2 and onset (except for methadone)
Duration of analgesic effect helps determine proper dosing frequency
IV fentanyl
Methadone: long-acting product**half-life can be long but analgesic effect lasts 4 – 8 h

11. Opioid Usual Starting Dose Comments
Fentanyl*
25 – 100 mcg IV q1h, then
1 – 2 mcg/kg/h
Patch: NOT for acute pain & NOT for opioid-naïve pts; do not cut patch in half
Hydromorphone (Dilaudid)
0.5 – 1 mg q4h IV
1 – 2 mg q4h PO
Very potent; preferred in pts with renal impairment
Methadone
5 mg q8-12h PO
Monitor for QT prolongation & drug interactions
Morphine
2 – 5 mg q4h IV
5 – 10 mg q4h PO (IR)
15 – 30 mg q8 or 12h (SR)
MSContin: NOT for acute pain; do not split/crush tablets
Meperidine (Demerol)
50 mg q3-4h PO/IV
NOT recommended for chronic use
Codeine
30 – 60 mg q4h PO
Has more side effects than morphine
Oxycodone
5 mg q4h PO (IR)
10 – 20 mg q12h (SR)
OxyContin: NOT for acute pain; do not split/crush tablets
Hydrocodone
5 – 10 mg q4h PO
always combined with APAP or ibuprofen – which limits its dosing
**fentanyl: different indications (adjuvant for general anesthesia maintenance, minor & major surgical procedures, control of post-op pain
Fentanyl patch dose will vary
MSContin & OxyContin dose will vary depending upon narcotic requirement
MSContin can be dosed q8 to q12h
Codeine has more side effects than morphine – more nausea and constipation

12. Opioid Available Doses
Fentanyl
IV: 25, 50, 100 mcg/ml
Patch: 25, 50, 75, 100 mcg
Hydromorphone (Dilaudid)
IV: 2 mg/ml; PCA: 1mg/ml & 0.2 mg/ml
PO: 2 mg
Methadone
PO: 5, 10 mg
Morphine
IV: 4 mg/ml; PCA: 1 mg/ml & 5 mg/ml
PO: IR 15, 30 mg
PO: ER (MS Contin): 15, 30, 60, 100 mg
Solution (Roxanol): 20 & 2 mg/ml
Meperidine (Demerol)
IV: 25, 50, 100 mg/ml
Codeine
PO: 30 mg
Oxycodone
PO: IR 5mg
PO: ER (OxyContin): 10, 20, 40, 80 mg
Solution (Roxicodone): 20 & 1 mg/ml
Oxycodone/APAP (Percocet)
PO: 5mg oxycodone/325 mg APAP
Hydrocodone/APAP (Norco)
PO: 5mg hydrocodone/325 mg APAP
Point out MSContin, OxyContin, Solutions
Hydrocodone/APAP: Lortab, Vicodine with 500 mg APAP are no longer formulary
Demerol 50 mg tabs no longer formulary

13. PCA Dosing Dosing considerations
For opioid-naïve patients, use lower end of range
Pain Assessment
Respiratory Assessment
Sedation Assessment
Drug
(standard concentrations)
Usual Demand
Dose
Range of Demand Dose
Lockout Interval (min)
Usual Basal Rate
Morphine
(1mg/ml and 5 mg/ml)
1.0 mg mg
5 - 15
None or
1 – 2 mg/hr
Hydromorphone (Dilaudid)
(0.1 mg/ml and 1 mg/ml)
0.2 mg mg
0.1 – 0.4 mg/hr
Loading dose can be used (particularly post-op)
Morphine LD: 5 – 10 mg
Dilaudid LD: 0.5 – 1.5 mg
Patients who are considered opioid-tolerant are those who have been taking, for a week or longer, at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral HYDROmorphone daily, or an equianalgesic dose of another opioid.” (Food and Drug Administration)
Fentanyl PCA: usual demand doses: 10 to 50 mcg; standard concentration of PCA is 50 mcg/ml
When initiating PCA for first time (no conversion from outpatient med), the initial demand dose is 50% of the basal rate

14. PCA dosing
62 yo patient s/p TAH has been moved to PACU. You have been asked to start the patient on a PCA. Which of the following is an appropriate order:
Morphine PCA 1 mg/ml: LD 2 mg, 1 mg demand dose, lock out 10 min, no basal
Dilaudid PCA 1mg/ml: LD 2 mg, 1 mg demand dose, lock out 10 min, no basal
Fentanyl patch 25 mcg q72 hours
initial
Remember: IV Dilaudid is about 7x more potent than IV morphine
Fentanyl is not indicated for post-op or acute pain

15. Conversions* Opioid Parenteral Oral Fentanyl 0.1 mg NA
Hydromorphone (Dilaudid)
1.5 mg
7.5 mg
Methadone** mg
mg***
Morphine
10 mg
30 mg
Meperidine (Demerol) mg
300 mg
Codeine
120 mg
200 mg
Oxycodone
20 mg
Hydrocodone
Decreasing IV potency as you go down the table
Dilaudid more potent than morphine or oxycodone
IV dilaudid to po: multiply by 5
IV morphine to po: multiply by 3
IV dilaudid is about 7x more potent than IV morphine
PO dilaudid is about 4x more potent than po morphine
*When switching between opioids, there is NOT a complete cross tolerance. If patient is controlled, consider decrease the dose by 1/2 to 1/3 to avoid side effects.
**conversion ratio is highly variable

16. Initial Fentanyl Patch Dose Conversion
PO 24-hour morphine (mg/day)
Fentanyl Patch Dose (mcg/hr)
45-134 25 50 75
100
125
150
175
200
225
250
275
300
Note: this is to change TO a fentanyl patch and not FROM the patch
For CHRONIC pain: 25 mcg/hr fentanyl patch = oral morphine 50 mg/24h

17. Fentanyl patch NOT for acute pain or post-op pain
Absorbed through the skin, producing a drug depot in the upper skin layers, then diffusing into systemic circulation
Can have variable responses between patients (i.e. cachetic, elderly)
Watch for drugs that inhibit its metabolism
Ketoconazole, erythromycin, diltiazem, grapefruit juice
Should be used with caution in elderly, cachetic, debilitated patients as they may have altered PKS due to poor fat stores, muscle wasting, or altered clearance
Up to 25% variability in absorption between patients
**avoid exposing application site to external heating source – heated water bed, heating pads, electric blanket, hot tub, heat lamps

18. Morphine:methadone conversion
Oral morphine-equivalent daily dose (mg/day)
Initial Dose Ratio
(oral morphine:oral methadone)
<30
2:1
30 – 99
4:1
100 – 299
8:1
300 – 499
12:1
500 – 999
15:1
>1000
20:1 or greater
ie. 360 mg morphine equivalents daily
Using table, divide by 12 to get 30 (360 divided by 12 = 30)
So would use methadone 10 mg tid

19. Breakthrough Dosing Use immediate-release opioids Chronic oral meds
Give 10 – 20% of the total daily dose q4hprn
Example – MS Contin 60 mg PO q12h – should give 10 – 20 mg q4h prn of morphine immediate release
IV dosing (PCA dosing)
10% of the 24 hr requirement, then:
Divide by 4 if giving every 15 minutes
Ex: 100 mg morphine daily  2.5 mg IV q15 min
MSContin: 120 mg total (10% is 12 mg and 20% is 24 mg)
IV dosing: 100 mg morphine daily:
10% is 10 mg
¼ of 10 mg = 2.5 mg

20. Dose Adjustment Increasing the opioid dosage
For moderate to severe pain, increase by – 100%
For mild to moderate pain, increase by – 50%
Convert to oral as early as possible:
Pain is controlled
GI function intact
IV to oral dosage calculation
Calculate total daily IV use
Calculate breakthrough dose
10-20% of total daily dose of regularly scheduled opioid every 4 h as needed

21. Conversion problem Pt is taking Percocet 5/325 two tabs q6h
What dose of oxycodone ER (OxyContin) would you start the patient?
What dose of morphine ER (MS Contin)?
What dose of fentanyl patch?

22. Conversion problem 8 tabs Percocet = 40 mg oxycodone per day
Oxycodone ER (OxyContin) = 20mg q12h
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23. Conversion Problem MS Contin conversion Fentanyl patch
40 mg po oxycodone = mg po oxycodone
x mg po morphine
X = 60 mg po morphine daily = MS Contin 30 mg q12h
If you want to decrease dose to allow for decreased cross-tolerance, decrease dose by 1/2 to 1/3 = 30 to 40 mg morphine daily = MS Contin 15 mg q12h
Fentanyl patch
30 – 60 mg po morphine daily = 25 mcg fentanyl patch
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24. Conversion problem
In the previous problem, your patient was stable on MS Contin 30 mg q12h
Your attending wants to change over to the fentanyl patch
How do you time the transition from MS Contin to the patch?

25. Conversion problem
In the previous problem, your patient was stable on MS Contin 30 mg q12h
Your attending wants to change over to the fentanyl patch
How do you time the transition from MS Contin to the patch?
It takes about 12 hrs for onset of fentanyl patch
Give patient one last dose of MS Contin at the same time the patch is applied
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26. Example of conversion from oral med to PCA
Pt taking OxyIR 20 mg PO q4h
Pt’s pain is well-controlled
Want to convert to hydromorphone PCA
What would be a basal dose (in mg/hr)?
What would be the bolus/demand dose?

27. Example of conversion of oral med to PCA
Pt taking OxyIR 20 mg q4h
Convert total oral daily dose (120 mg oxycodone) to oral hydromorphone
120 mg po oxycodone = 20 mg po oxycodone
x 7.5 mg po hydromorphone
X = 45 mg po hydromorphone
Convert to IV
45 mg po hydromorphone = 7.5 mg po
x mg IV
x = 9 mg IV hydromorphone daily
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28. Example of conversion to PCA
Basal rate
9 mg daily total = 0.4 mg per hour
May want to decrease basal by 1/2 to 1/3 to account for incomplete cross tolerance
Basal dose of 0.2 to 0.3 mg per hour
Bolus/demand dose is usually 10% of the daily dose divided by 4
(0.10 x 9 mg) / 4 = 0.2 mg q 15 minutes
Titrate based on use & pt’s response
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29. Example of PCA conversion to oral med
Pt on post-op morphine PCA with basal of 1 mg/hr and bolus of 1 mg q15 minutes
Pt used 40 bolus injections in 24 hours
What dose of oral morphine (basal & breakthrough) should be used?
What dose of oral oxycodone (basal & breakthrough) should be used?

30. Example of PCA conversion to oral med
Total daily use of IV morphine
1 mg/h x 24 h + 40 bolus = 64 mg/24 hour
Convert to oral morphine
64 mg IV morphine = 1 mg IV morphine
x 3 mg po morphine
X = 192 mg po morphine
MS Contin 100 mg q12h (basal)
Morphine IR 30 mg q4h prn for breakthrough
10 – 20% of daily dose q4h (10 – 20% of 200 mg is 20 to 40 mg)
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31. Example of PCA conversion to oral med
Converting to po oxycodone
192 mg po morphine = 30 mg po morphine
x 20 mg po oxycodone
X = 128 mg po oxycodone
Decrease daily dose by 1/2 or 1/3 to allow for incomplete cross tolerance
Total daily dose of oxycodone = 64 to 85 mg
OxyContin dose (basal): 60 mg q12h or can use 30 to 40 mg q12h if want to account for incomplete cross tolerance
Oxycodone IR (breakthrough): 5-10 mg q4h prn
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32. Side Effects Constipation – worsens with dose increases
Sedation, fatigue – wears off within 1 week
Dizziness – wears off, may require slower titration
Nausea – usually wears off; switching products may help
Hallucinations – more common at higher doses
Itching - anti-histamine; rotate narcotics
Respiratory depression – rare side effect with chronic dosing; more common with IV, epidural
Tolerance to side effects (except to constipation, resp depression) develop within a week of therapy

33. Respiratory Depression
0.2 – 2 mg naloxone IV, IM, SC
Repeat doses every 2 to 3 min prn
Total dose up to 10 mg
After reversal, may need to readminister dose at a later interval (20 to 60 minutes) depending on the type/duration of opioid
Usual dose is 0.4 mg and IV route is preferred
IV can be given via endotracheal
Onset of action: IV: minutes
Duration: 30 to 120 minutes depending on dose and route
Half-life: 30 – 90 minutes

34. Assessment Scales Respiratory Sedation
Should be counted for at least 30 seconds
If RR <12/min, then count for full minute
If RR <10/min, stop PCA
If RR <4/min, give naloxone
1 = agitated, restless
2 = cooperative, oriented
3 = asleep, easily arousable
4 = asleep, arouses to voice
5 = no response to verbal stimuli
6 = no response to pain
Stop PCA & give naloxone for score 5 & 6
Respiratory Rate: Should be counted for 30 seconds and if respiratory rate is less than 12/minute, then it should be counted for a full minute. Respiratory rates vary a great deal, and normal has quite a wide range. Regarding PCA use, a respiratory rate below 8/minute should concern anyone. A rate below 9/minute is probably where most clinicians would draw the line, but many policies use 10/minute as a cut-off where
opioids would be discontinued. The rate of respiration assessment should be made in context with sedation and pain assessments.

35. Constipation Need a stool softener Need a stimulant laxative
Docusate 100 mg: 1 to 2 caps po twice daily
Need a stimulant laxative
Senna: usual dose is 1 tab at bedtime or twice daily but can titrate up to 4 tabs three times daily prn
Bisacodyl 5 mg: 1 to 2 tabs twice daily prn

36. Constipation Medication Dose Polyethylene Glycol (Miralax)
17 g in 8oz water daily to twice daily
Milk of Magnesia
30 – 60 ml daily to twice daily
Lactulose
20 – 60 ml twice to four times daily
Magnesium Citrate**
8oz daily
Bisacodyl suppositories
Daily to twice daily
Fleet enemas
Mag citrate should not be used regularly as a daily product

37. Opioid “Allergy”
“Pseudoallergy” caused by histamine release – most commonly seen with codeine, morphine, meperidine
Pt c/o flushing, itching, hives, sweating
Mild hypotension
Use H2RA
Decrease dose
Switch to a more potent opioid (i.e. fentanyl, hydromorphone)

38. Opioid “Allergy” Pts with “true” allergy Switch to a different class
Breathing, speaking, swallowing difficulties
Swelling of face, lips, mouth, tongue, pharnyx, or larynx
Severe hypotension
Switch to a different class
Phenylpiperidines: meperidine, fentanyl
Diphenylheptanes: methadone, propoxyphene
Morphine group: morphine, codeine, hydrocodone, oxycodone, hydromorphone, nalbuphine, butorphanol

39. Sole Provider Program Purpose
To monitor patients exhibiting signs of drug-seeking behavior, insufficient analgesia, evidence of non-optimization in care options, psychosocial issues, or other complex pharmaceutical care issues
Narcotic prescriptions only
The primary care provider can be the Sole Provider or choose to refer a patient to a Sole Provider
Opioid “contract” signed between patient and Sole Provider physician
Pharmacy informed and note put in CHCS
Sole Provider committee will monitor for violations
SPP for narcotics only (not for benzos)
1. Program designed to assist patients with managing complex therapy/regimen involving controlled substances and to prevent unintended use.
2. Pharmacist runs a monthly report then meet with a group of providers to identify patients with need.
3. Patients identified as needing assistance will be assigned a Primary Care Manager (PCM). PCM will discuss care with patient and will issue a pain contract.
4. Pharmacist assigned to Sole Provider Program (Dr. Albert Ly - currently) will identify patients in CHCS by entering "Sole Provider" as a medication in the patient's profile. The direction for this "Sole Provider" medication will identify the PCM and his/her contact info and an alternate provider in case the PCM is not present. The pharmacist will also add a comment in the patient's profile (PPC comment) to reflect Sole Provider Program enrollment. And lastly, the pharmacist will add an "allergy" in the patient's profile so that providers can see the warning that the patient is enrolled in the
program. Example of allergy may include Percocet with a comment "Not true allergy to med. Sole Provider Program. Controlled Rx from Dr. XXX only.“

40. Sole Provider Program
NNMC Intranet
Site Map
Pharmacy

41. Sole Provider Program

42. Writing Prescriptions
Link on Pharmacy Website
Write legibly
Write out your DEA number
Spell out the quantity to be dispensed
C-IIs are not refilled (new Rx required) & require separate prescriptions
Use DoD Form 1289 for controlled substances

43. DEA numbers
Retail and mail-order pharmacies are no longer accepting the NNMC DEA number
Must apply for own practitioner DEA number
Active military physicians (MD, DO, DDS, DMD, and DPM) are fee exempt and may be licensed in any state to obtain a DEA registration
DEA number is to be used solely for DoD beneficiaries prescriptions and may not be used for off-duty employment

44. DEA numbers To apply for DEA number:
Contact the Credentialing Office to complete the correct paperwork
Contact person: Rebekah Byrd at

45. Med Errors to Avoid Roxanol v Roxicodone oral solutions PCA strength
Roxanol (morphine) v Roxicodone (oxycodone)
Correct strengths
PCA strength
Morphine: 1 mg/ml and 5 mg/ml
Hydromorphone: 1 mg/ml and 0.2 mg/ml
Fentanyl patch
For inpatients, double check if patient has patch on from home
Morphine: 20 & 2 mg/ml while oxycodone has 20 & 1 mg/ml

46. References
Pharmacotherapy: A Pathophysiologic Approach. 6th edition: Chapter 58.
End of Life/Palliative Education Resource Center
Micromedex
Drug Facts and Comparisons
Equianalgesic Dosing of Opioids for Pain Management. Pharmacist’s Letter 2004.
Opioid Intolerance Decision Algorithm. Pharmacist’s Letter 2006.
Clinical Pharmacology

47. References
Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain, American Pain Society, 5th Ed. 2003
Grammaitoni AR et al. Clinical Application of Opioid Equianalgesic Data. Clin J Pain 2003; 19(5):
McPherson M.L. Demystifying Opioid Conversion Calculations: A Guide for Effective Dosing

48. Questions?