Pain Management & Opioid Analgesics

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

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

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

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** www.anzsgm.org/vgmtp/Pain/analgesia_ladder.htm

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

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

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

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

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: 5 - 15 min PO: 30 min 3 – 5h Methadone** 8 – 59h 30 – 60 min 4 – 8h Morphine 2 – 4h IV:5 - 10 min PO (IR): 30 - 60 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

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

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

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 0.5-2.5 mg 5 - 15 None or 1 – 2 mg/hr Hydromorphone (Dilaudid) (0.1 mg/ml and 1 mg/ml) 0.2 mg 0.05-0.4 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

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

Conversions* Opioid Parenteral Oral Fentanyl 0.1 mg NA Hydromorphone (Dilaudid) 1.5 mg 7.5 mg Methadone** 5 - 10 mg 2 - 20 mg*** Morphine 10 mg 30 mg Meperidine (Demerol) 75 -100 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

Initial Fentanyl Patch Dose Conversion PO 24-hour morphine (mg/day) Fentanyl Patch Dose (mcg/hr) 45-134 25 135-224 50 225-314 75 315-404 100 405-494 125 495-584 150 585-674 175 675-764 200 765-854 225 855-944 250 945-1034 275 1035-1124 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

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

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

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

Dose Adjustment Increasing the opioid dosage For moderate to severe pain, increase by 50 – 100% For mild to moderate pain, increase by 25 – 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

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?

Conversion problem 8 tabs Percocet = 40 mg oxycodone per day Oxycodone ER (OxyContin) = 20mg q12h Hide slide for print out

Conversion Problem MS Contin conversion Fentanyl patch 40 mg po oxycodone = 20 mg po oxycodone x 30 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 Hide slide for print out

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?

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 Hide slide for print out

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?

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 1.5 mg IV x = 9 mg IV hydromorphone daily Hide slide for print out

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 Hide slide for print out

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?

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) Hide slide for print out

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 Hide slide for print out

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

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: 1 - 2 minutes Duration: 30 to 120 minutes depending on dose and route Half-life: 30 – 90 minutes

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.

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

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 www.toonpool.com

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)

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

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.“

Sole Provider Program NNMC Intranet Site Map Pharmacy

Sole Provider Program

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

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

DEA numbers To apply for DEA number: Contact the Credentialing Office to complete the correct paperwork Contact person: Rebekah Byrd at 319-4157

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

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

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): 286-297. McPherson M.L. Demystifying Opioid Conversion Calculations: A Guide for Effective Dosing. 2010.

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