Pain Management 101: Basic Skills for Opioid Prescribing Anthony J. Caprio, MD Assistant Professor of Medicine Division of Geriatric Medicine Center for Aging and Health Palliative Care Consultation Service University of North Carolina at Chapel

Objectives Examine the concept and assessment of pain Illustrate the differences between physical dependence, tolerance, addiction, and pseudo- addiction. Practice prescribing opioids for chronic and acute pain, titrate for adequate pain relief, and incorporate special dosing considerations Convert between different opioids and between different routes of administration Anticipate and treat side effects of opioids

“Illness is the doctor to whom we pay most heed; to kindness, to knowledge, we make promise only; pain we obey.” -Marcel Proust

Case: “Please Help Me!” Mrs. D. has breast cancer with bone metastases Received radiation to femur and ribs Pain previously controlled using Morphine Extended Release 30mg po q12h Morphine Immediate Release 5mg q4h prn pain Now has “excruciating” back and leg pain “Please help me! I just want to die!” What do you do?

Pain Assessment and Management Types of Pain Nociceptive Pain Somatic: Caused by activation of pain receptors (nociceptors) in the cutaneous or deep tissues (musculoskeletal) Visceral Pain: Poorly localized pain sensation from internal organs and structures (chest, abdomen, pelvis) Neuropathic Pain: Results from injury to nervous system (burning or tingling) T. Caprio University of Rochester 2009

Pain and Suffering Suffering is more than the physical experience of pain Physical, Emotional, Social, Existential contributions to the experience of suffering Duty of physicians to alleviate suffering Suffering can never be completely relieved by opioids

Tolerance Reduced effectiveness over time Tolerance to side effects is favorable Tolerance to analgesia is rarely significant When increasing doses required, suspect worsening disease rather than tolerance

Physical Dependence Withdrawal Symptoms produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug and/or administration of an antagonist Inevitable physiologic change from use of opioids NOT evidence of addiction

Addiction Psychological dependence Genetic, psychosocial, and environmental factors Characterized by one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Non-adherence to a therapeutic regimen Differentiate from under-treatment of pain, criminal drug diversion, and family dysfunction

Pseudo-addiction Mimics addictive behavior, but is due to the under treatment of pain hoarding medication seeking prescriptions from multiple providers repeatedly requesting more medication Behavior disappears with proper treatment

Assessing Severity of Pain Numerical Rating Do you have pain? How bad is your pain? 1 (mild) – 10 (severe) Another way to think about pain severity: Mild (1-3) Moderate (4-7) Severe (8-10)

Pain is Personal Pain ratings are relative to an individual One person’s “4/10” may be acceptable (allowing them to function reasonably well), while another person’s “4/10” may be debilitating. You need to understand and negotiate the level of pain control which will allow the patient to tolerate the pain and function reasonably well.

WHO 3-Step Analgesic Ladder WHO: World Health Organization (see www.who.int/cancer/palliative/painladder/en)

Starting Opioids Pick one drug and stick with it Avoid using multiple opioids simultaneously You won’t know which one is working or which one is causing adverse effects Very confusing (and expensive) for patients If effective, titrate drug for optimal effect If not effective (after appropriate dose escalation) or if limited by side-effects, switch to a different opioid Acute pain and chronic pain will have different dosing considerations

Opioid-Induced Constipation Never become tolerant and not necessarily dose- dependent ALL opioid prescriptions should be linked to a bowel regimen (make it routine) Stimulant laxative is often needed Stool softener may be helpful, but avoid “All Mush and No Push” Schedule senekot (Senna) and titrate as needed Give a specific plan: “If no BM in x days then take y; if still no BM, then take z” Methylnaltrexone is a peripherally-acting mu-opioid receptor antagonist Methylnaltrexone is SubQ, expensive; needs palliative care approval for use at UNC

Acute Pain Crisis “An event in which the patient reports pain that is severe, uncontrolled, and causing distress for the patient, family members, or both.” Requires a “rapid response” Reassess quickly and repeatedly frequency is determined by time to peak concentration of the opioid JAMA. 2008;299(12):1457-1467

Many Opioids Demonstrate First Order Kinetics Peak Plasma Concentrations (Cmax) Oral: 60 to 90 min SC or IM: 30 min IV: 6 minutes Half-Life (t1/2) Often depends on renal function Generally 3-4 hrs Many have active metabolites When dosed repeatedly, their plasma concentrations approach a steady state after 4 to 5 half-lives. Source: Emanuel LL, von Gunten CF, Ferris FD. EPEC curriculum, 1999.

Managing an Acute Pain Crisis Administer double the rescue (breakthrough) dose intravenously. Repeat same dose in 15 minutes if there is no or minimal pain relief. If pain persists at 7 or higher on a 10-point scale without adverse effects, increase the intravenous rescue dose by 50%. Continue to administer this dose every 15 minutes until patient experiences more than 50% pain relief or adverse effects develop. Because the analgesic effect is a logarithmic function of the dose of the opioid, a doubling of the dose in an opioid-tolerant patient may be needed. JAMA 2008;299:1457-1467

Titrating Opioids for Pain Relief For ongoing moderate to severe pain increase opioids doses by 50-100% For ongoing mild to moderate pain increase by 25- 50% When dose escalating long-acting opioids or opioid (continuous) infusions, do not increase the long- acting drug or infusion basal rate more than 100% at any one time Use short-acting medications for breakthrough pain, keep track of these extra doses and use this information to adjust doses Lasix analogy Source: Fast Fact #020 www.eperc.mcw.edu

Breakthrough Medications Generally 10% of the total daily dose Divided into intervals based on the route of administration and onset to peak analgesia (ie. q4hours for oral medications) More frequent intervals may be necessary Generally, if a patient is requiring more than 3-4 breakthrough doses per day, you should consider increasing the long-acting dose

Other Dosing Considerations Theoretically no ceiling dose for opioids Elderly Lower doses of any drug may be necessary Caution with NSAIDs (bleeding and renal effects) Tylenol 3g/day maximum Caution with neuropathic pain medications (start low and go slow; avoid tricyclic antidepressants) Renal failure Consider 25-50% dose reductions for opioids Fentanyl and methadone are safest Hydromorphone (Dilaudid) is a reasonable choice Oxycodone should be used with caution (can accumulate) Do Not Use meperidine (Demerol)

Changing Route of Administration Parenteral (IV/IM) is more potent than oral (po) Intravenous and subcutaneous dosing are usually similar Oral : Parenteral Morphine 3 : 1 Hydromorphone 5 - 8 : 1 (wide range)

Case: Mrs. D. Calculate 24-hour oral morphine use: Morphine 30mg po q12h = 60mg/24h Morphine 5mg every 4h (prn)  30mg/24h Total: 90mg oral morphine equivalents/24h Convert to IV morphine 90mg oral morphine = 30mg iv morphine Calculate Breakthrough Dose 10% of 30mg = 3mg iv (give q10-15min prn)

Case: Mrs. D’s Pain Crisis Pain is 10/10 Double dose of the prn Give at least 6mg iv x 1 now Re-evaluate in 15 minutes Pain still rated 10/10 Give another 6mg iv x 1 Pain rated 8/10 Consider giving 9mg iv (50% increase) Re-evaluate pain in 15 minutes Pain rated 5/10 50% reduction of her pain with 21mg iv morphine over 45 minutes

Indications for Changing Opioids Intolerable adverse effects Poor analgesic efficacy despite dose titration Drug-drug interactions Preference or need for a different route of administration Change in clinical status or clinical setting that necessitates an opioid with different properties Financial or drug-availability considerations J Pain Symptom Manage 2009;38:418-425.

Common Adverse Effects Pain Assessment and Management Common Adverse Effects Constipation Nausea Common adverse effect, not an allergy Try antiemtics, trying other opioid or adjusting dose Likely will become tolerant to these effects Consider other causes of nausea like chemo and constipation Sedation Tolerance usually develops in 24-72 hours Appears well before respiratory depression Decrease dose or increase interval Caution when starting neuropathic pain medications (additive effects) Consider other sources of fatigue and sedation (disease progression, process of dying) Nausea: mechanism: stimulates chemoreceptor trigger zone (4th ventricle), stimulate vestibular apparatus, constipation stimulates afferent cholinergic pathways T. Caprio University of Rochester 2009

Other Adverse Effects Urinary retention Delirium Myoclonus Consider rotating opioid, try lower doses Avoid anticholinergics and sedatives Myoclonus observed with renal insufficiency, hepatic insufficiency, and high opioid doses Switch opioids, correct electrolytes if possible Benzodiazepines may be helpful

Equianalgesic Dosing No “one-size fits all” approach Genetic differences may account for variance Pain is complex and often has many components Starting doses and equianalgesic conversions are educated guesses (at best) Assume that you will need to adjust up or down based on clinical judgment Codeine example: about 10% of the Caucasian population lacks sufficient levels of a key CYP450 enzyme to convert codeine to morphine and therefore derive no significant analgesia from codeine

Equianalgesic Table Not based on much evidence Large variability observed Table does not replace clinical judgment You need to think and reassess, not just plug-in numbers and write orders! J Pain Symptom Manage 2009;38:426-439

UNC HealthCare “Pain Card” http://pharmacy.intranet.unchealthcare.org/clinresources/clinguidelines/pain.pdf

Equianalgesic Dosing: More Than Just Reading the Table Step 1: Calculate equianalgesic dose from table Apply “safety factor”: 25 - 50% automatic reduction to account for incomplete cross-tolerance and individual variation Exceptions: methadone (reduce more), transdermal fentanyl patch (safety factor built-in to conversion tables) and transmucosal fentanyl (use lowest dose) Step 2: Consider severity of the pain and other medical or psychosocial factors that potentially alter potency or shift the likelihood that the initial dose of the new drug will be analgesic, relatively free of adverse effects, and unlikely to precipitate withdrawal Determine whether to apply an additional increase or decrease of 15% - 30% J Pain Symptom Manage 2009;38:418-425.

Case: Mrs. D. Eventually titrated to morphine PCA 6mg/h iv over then next 2 days with better pain control but increased itching and “jerking” noted Convert to oral oxycodone Morphine iv 6mg/h x 24h = 144mg Oral morphine equivalents = 432mg Oxycodone (oral) : Morphine (oral) = 1 : 1.5 Set-up ratio and then X= 432/1.5 = 288mg Oxycodone equianlagesic dose = 288mg

Case: Dosing Considerations Reduce dose by 50% for incomplete cross-tolerance Increase dose by 20% based on your clinical judgment Normal renal and hepatic function Severe pain coming into hospital, still not optimally controlled No problems with sedation Good social support and will be monitored at home Net effect is dose reduction by 30% 30% of Oxycodone 288mg ≈ 200mg Prescribe Oxycodone Sustained Release 100mg po q12h Oxycodone Immediate Release 20mg po q4h prn breakthrough pain (10% of 200mg = 20mg) Reduce by 25-50% for incomplete cross-tolerance Increaser or reduce by 15-30% based on clinical judgment

Patient-Controlled Analgesia (PCA) Advantages: Quick administration Patient “in-control” Record of demands to help with dose titration Disadvantages: can’t be used by delirious patients or those with an altered LOC reduces an important element of nursing pain assessment patient may avoid demands Dosing considerations basal vs. demand basal + demand Need to review PCA logs and interpret the MAR

Patient-Controlled Analgesia (PCA) Orders Continuous infusion Rate: mg/hr or mcg/hr -Depends on whether patient is opioid naïve, nature of the pain, and any previous information about opioid needs Demand Dose: mg or mcg (‘patient initiated dose,’ ‘patient demand dose,’ or ‘bolus dose’) -Based on patterns of breakthrough pain, consider a bolus dose of 50% - 150% of the hourly rate Dosing Interval (Delay Interval): minutes -Peak analgesic effect from an IV bolus dose is 5-10 minutes -Should be in the range of 10-20 minutes Hour Limit: mg or mcg -Maximum amount of drug to be dispensed in a defined period of time -Often set to deliver 3-5 times the estimated required hourly dose

Methadone NMDA receptor antagonist and mu-opioid receptor agonist properties Decreasing opioid tolerance Attenuating neuropathic pain No active metabolites, not removed by dialysis Inexpensive and Long-acting Disadvantages Non-linear conversion Risk for overdose (by both prescribers and patients) Many drug interactions QTc prolongation ASK for help with dosing!!

Pitfalls Under-treated pain Long-acting vs. short-acting opioids Avoiding opioids or not increasing the dose of an opioid Too long of an interval between breakthrough doses Long-acting vs. short-acting opioids Starting long-acting opioids in a opioid-naïve patient Using long-acting medications for breakthrough pain Precipitating opioid-withdrawal by abruptly stopping (or dose- reducing) opioids Treating patients with opioids but missing other sources of suffering Methadone dosing without understanding pharmacokinetics Potentially exceeding 4g of acetaminophen/day (3g/day in elderly)

Mrs. D. PCA morphine is reduced and then discontinued after po oxycodone sustained release is started Myoclonus and itching resolve Pain is generally 2-3/10 with exacerbations up to 6/10, treated with immediate release oxycodone Also started on dexamethasone and evaluated for additional radiation therapy Discharged home with outpatient follow-up Taking about 2-3 immediate release oxycodone daily and able to care for herself and family

Summary All patients on chronic opioid therapy will develop physical dependence Tolerance develops Withdrawal symptoms if opioid is stopped Few patients will become addicted to opioids with appropriate prescribing and assessments Pseudo-addictive behavior related to the under-treatment of pain

Summary (cont’d) Pain crisis may require repeated q15min iv opioid dosing until pain <7/10 or 50% reduction in pain scores Titrate opioids based on severity of pain Breakthrough about 10% of total daily dose given as short-acting opioid PRN; for oral opioids generally no longer than q4h dosing intervals If >3-4 breakthrough doses per day, need to titrate long-acting opioids

Summary (cont’d) Try to use only one drug at a time Parenteral is more potent than oral Use equianalgesic tables with caution Automatic dose reduction by 25-50% Increase or decrease by 15-30% based on clinical judgment Dose-reduce for advanced age and renal impairment Ask for help with methadone dosing Bowel regimen with every opioid prescription!!

Closing Thoughts Patients are different; pain relief and side effects will vary with the same dose of the same medication Incomplete or inconsistent literature regarding dosing, conversions, and equianalgesic tables Clinical judgment is key; no card, lecture, or consultant can replace good judgment Good judgment comes from thoughtfulness, careful observation/assessments, and lots of practice Suffering is more than the physical experience of pain; suffering can never be completely relieved by opioids