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

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

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

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): 1685-90.

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 www.epec.net

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) 1124-1132.

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.

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 2.5-5 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.

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

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.

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

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

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):1943-53. 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

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

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

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

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

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.

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

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

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

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

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

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

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

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

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

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