1. General Drug Information for ER/LA Analgesic Products
Unit 5
Joseph Shega, MD

2. Universal Black-Box Warning ER/LA
Abuse Potential
Life-threatening respiratory depression
Initiation
Dose increase
Accidental exposure
Interaction with alcohol
Accidental exposure and death especially in children

3. Objectives Pharmacokinetics and Pharmacodynamics
Identify adverse effects of ER/LA opioids
Most common constipation
Life threatening
Respiratory depression
QTc prolongation
Product manipulation
Transdermal
Tablets
Capsules
Products and dosages for opioid naïve and tolerant

4. Morphine Pharmacology/Pharmacokinetics
Block the release of neurotransmitters in the spinal cord
Mu, delta, kappa
Conjugated in liver
Excreted via kidney (90%–95%)
First-order kinetics
Conjugation in liver for morphine, hydromorphone, oxymorphone, and tapentadol
Oxidized via cytochrome p450’s include burophenine, methadone, fentanyl, and oxycodone
Stein, C. The control of pain in peripheral tissues by opioids. NEJM 332 (25):

5. Cmax Half-life (t1/2) IV SC / IM Plasma Concentration po / pr Time
This picture demontrates that for most opiates that are considered short-acting (MSIR, Oxycodone, Hydrocodone, dilaudid) the half-life is about the same no matter the route of administration. What does differ is the Cmax or the time it takes to reach maximal concentration. Once the drug has reached Cmax there will not be any additional analgesia. This becomes important when we discuss the appropriate time to give a “breakthrough dose”.
Half-life (t1/2)
Time
From Education on Palliative and End of Life Care (EPEC), available at

6. Morphine pharmacology . . .
Cmax (peak) after
po, pr  1 h
SC, IM  30 min
IV  6 – 15 min
half-life at steady state
po / po / SC / IM / IV  3-4 h
Whenever possible always use oral route of administration. Here are the time intervals for Cmax.
Levy, M. Drug Therapy: Pharmacologic treatment of cancer pain. NEJM 1996; 335 (15)

7. Short Acting Opioids Steady state after 4–5 half-lives
steady state after 1 day (24 hours)
Duration of effect of “immediate-release” formulations (except methadone)
3–5 hours po / pr
shorter with parenteral bolus (1-2 hours)
It takes about 4-5 half-lives (one day for short acting meds who have duration of effect of 3-4 hours). Long acting meds (Oxycontin, MSContin) which have a duration of effect of 8-12 hours could take several days to reach steady state. That is why it is best to start an opiate naïve patient on a short-acting med. One can titrate up faster and get them to steady state in a more timely fashion.

8. Long Acting Opioids Duration of effect preparation specific
Capsules/tablets 12 to 24 hrs
Methadone 6-8 hours
Patch
Fentantyl 72hrs
Buprenorphine 1 week
Steady State
Days for most preparations
Methadone up to one week
Effective starting dose should be based on patient’s age, body weight, and degree of cachexia as well as the total daily dose of previous analgesics and frequency and severity of pain. While on short-acting po meds, the breakthrough dose should be ½ - 1 tab of what is used around the clock. Example: pt getting 10 mg liquid morphine every 4 hours. If patient has normal metabolic function can give 5 – 10 mg po for breakthrough every hour as needed (less often like every 90 minutes if significant renal/hepatic impairment).
Example: Morphine elixir 5mg po every 4 hours standing. Breakthrough dose mg po every 1 hour (Cmax) as needed. In order to avoid having someone wake up in the middle of the night to take a pain pill he/she can take an extra dose at bedtime (Morphine elixir 10mg at bedtime).
For elderly rule is to start low and go slow, titrate up as needed and rapidly if pt has decent renal function. The main rule is to observe pt. frequently throughout the first 24 hours of therapy and make appropriate dose adjustments.
Do NOT start with long-acting opiate or patch in someone who is opiate naïve.

9. Appropriate Patient Selection LA/ER
Opioid tolerant, generally not naive
Avoid in acute pain
Avoid when short duration anticipated
Avoid post-op pain management
Not for use in mild pain
Point out a few exceptions about niave patients and LA opioids may try

10. Opioid adverse effects
Common Uncommon
Constipation Respiratory depression
Dry mouth Bad dreams / hallucinations
Nausea / vomiting Dysphoria / delirium
Sedation Myoclonus / seizures
Sweats Pruritus / urticaria
Urinary retention
SIADH
Julie: I put respiratory depression at the top of the uncommon side effects because, per the FDA blueprint, it is the most important serious adverse effect because it can be immediately life-threatening.

11. Constipation
Most common adverse effect encountered during chronic opioid therapy
No tolerance developes to this side effect
Multifactorial
Peripheral and central opioid effect
Drug-Drug interactions (anticholinergics)
Decreased mobility
PREVENTION IS KEY!
Talk about additive effects of anticholinergic medications such as those used to treat urinary urgency or tricyclics or calcium channel blockers
Also, think about patients who are not as ambulatory
Decreased peristalsis, decreased GI secretions, increased tone ileocecal valve and decrease in defecation reflux, decreased sensation rectal fullness 35

12. Constipation: Management
Surfactants (softeners)
Docusate
Stimulants
Senna
Biscadoyl (Dulcolox)
Osmotic Laxatives
Magnesium/aluminum salts
Lactulose
Sorbitol
Enemas
Opioid-receptor antagonists (other approaches fail)
Note, fiber is not on the list and should not be used 36

13. Tolerance to Opioids Tolerance to analgesic effects is rare
Tolerance is defined as decreasing response to a drug as a consequence of its continued use*
Tolerance to analgesic effects is rare
Doses remain unchanged when pain stimulus is stable
Tolerance to side effects typical (except constipation)
Disease progression (not tolerance), should be suspected when increasing doses are required for pain control
* Oxford Textbook of Palliative Medicine, 3rd Ed. 2004Ballantyne and Mao, NEJM 349(20):
Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of a drug’s effects over time. Clinically significant tolerance is unusual because the therapeutic range of opioids is very wide. After an effective baseline dose is established dose requirements usually plateau until disease progression occurs, at which time increased doses are usually necessary to control increased levels of pain.
Opiod tolerate doses
Morphine 60mg, oxycodone 30mg, hydromorphone 8mg daily

14. Initiating LA/ER Products in Opioid Naive
Specific product information for most LA/ER preparations
Certain strengths
Certain doses
Not recommended (must be tolerant)
Fentanyl patch
ER Hydromorphone

15. Opioids and Respiratory Depression
CNS depressants
Alcohol
Sedatives
Hypnotics
Tranquilizers
Tricyclic antidepressants
Muscle relaxants
Alcohol and rapid release of opioid via dumping
MAOIs and respiratory depression (also serotonin syndrome)
Can be life threatenting
Or sedation
Opioids with serotinergic activity- fentanyl, methadone and tapentadol

16. Transdermal Preparations
Increased absorption leading to fatal overdoses
External heat- pad, hot tub
Fever
Exertion
Metal foil backings not safe for use in MRIs.

17. Additional Drug Interactions
Opioids reduce diuretic efficacy via ADH release
Water retention at collecting ducts
QTc interval prolongation
Methadone
Buprenorphine
Opioids and risk of urinary retention
Cytochrome P450 inhibitors or inducers, increase or decrease opioid blood levels that are oxidized
Increase in ADH (antidiuretic hormone) causes water retention in collecting duct
QT prolongation is dose dependent
Phase 1 oxidation
Phase 2 glocuronidation morphine, hydromorphone, and oxymorphone

18. Product Manipulation ER/LA Opioids
Tablets
Must be swallowed whole
Capsules
Must be swallowed intact
Sprinkle on applesauce
No chewing
Nursing staff often a barrier, especially when uncomfortable with scheduled narcotics and those at higher doses.
Assessment holds true even more so in persons with cognitive impairment who may not be able to verbalize their complaints or may respond to pain by change in behaviors that are misinterpreted as secondary to the dementia.

19. Question #1
1. Which of the following does NOT accurately describe a potential drug-drug interaction involving an ER/LA opioid?
Certain opioids, such as buprenorphine, can prolong the QTc interval
Drugs that inhibit or induce certain cytochrome P450 enzymes can affect the blood levels of certain opioids
Opioids can potentiate the efficacy of diuretics by blocking the release of antidiuretic hormone
Concomitant use of a monoamine oxidase (MAO) inhibitor can increase the risk of respiratory depression

20. Question #1
1. Which of the following does NOT accurately describe a potential drug-drug interaction involving an ER/LA opioid?
Certain opioids, such as buprenorphine, can prolong the QTc interval
Drugs that inhibit or induce certain cytochrome P450 enzymes can affect the blood levels of certain opioids
Opioids can potentiate the efficacy of diuretics by blocking the release of antidiuretic hormone
Concomitant use of a monoamine oxidase (MAO) inhibitor can increase the risk of respiratory depression

21. Question #2
2. Patients must be opioid tolerant before using which of the following opioid formulations?
Transdermal fentanyl, any strength
Transdermal buprenorphine, any strength
ER morphine sulfate, 45 mg or higher
ER hydromorphone, 16 mg only

22. Question #2
2. Patients must be opioid tolerant before using which of the following opioid formulations?
Transdermal fentanyl, any strength
Transdermal buprenorphine, any strength
ER morphine sulfate, 45 mg or higher
ER hydromorphone, 16 mg only
Tolerance to sedating and respiratory-depressant effects of opioids is critical to the safe use of certain products, certain dosage unit strengths, or certain doses of some products

23. Question #3
4. A patient with chronic pain syndrome has uncontrolled pain and after evaluation is considered to be an appropriate candidate for a trial of ER/LA opioid therapy. The patient has cardiac arrhythmia, hypertension, and depression and is currently on 7.5/500 mg hydrocodone with acetaminophen 3x/day. Which of the following is the safest ER/LA option for this patient?
Buprenorphine
Oxycodone
Methadone
Double current dose of hydrocodone

24. Question #3
4. A patient with chronic pain syndrome has uncontrolled pain and after evaluation is considered to be an appropriate candidate for a trial of ER/LA opioid therapy. The patient has cardiac arrhythmia, hypertension, and depression and is currently on 7.5/500 mg hydrocodone with acetaminophen 3x/day. Which of the following is the safest ER/LA option for this patient?
Buprenorphine
Oxycodone
Methadone
Double current dose of hydrocodone

25. Question #4
5. Among patients on long-term opioid therapy, which behavior is likely to be the safest?
Patient on oxycodone ER 100 mg 3 x d who rarely drinks and has 8 beers at a high school reunion
Patient on a stable dose of 100 mg MS Contin twice daily who drives to and from work every day
Patient with a fentanyl patch who uses a hot tub every night
Patient who crushes her ER/LA oxycodone into her applesauce to make it easier to swallow

26. Question #4
5. Among patients on long-term opioid therapy, which behavior is likely to be the safest?
Patient on oxycodone ER 100 mg 3 x d who rarely drinks and has 8 beers at a high school reunion
Patient on a stable dose of 100 mg MS Contin twice daily who drives to and from work every day
Patient with a fentanyl patch who uses a hot tub every night
Patient who crushes her ER/LA oxycodone into her applesauce to make it easier to swallow

27. Question #5 Confusion Sedation Constipation Nausea
6. A patient with chronic pain has been taking an ER/LA opioid for 6 months. Which of the following side effects would most likely persist?
Confusion
Sedation
Constipation
Nausea

28. Question #5
6. A patient with chronic pain has been taking an ER/LA opioid for 6 months. Which of the following side effects would most likely persist?
Confusion
Sedation
Constipation
Nausea