2Learning Objectives Understand the spectrum of pain pharmacology Choose pharmacologic treatment options in chronic and cancer painIdentify the more common side effects and strategies to manage those side effects
3Mr. Pain’s Story57 yr. old male diagnosed with small cell lung cancer. Has a lg. mass in his LUL along with mediastinal & (lt.) hilar adenopathy, extensive liver mets.MI in takes ASA daily; peptic ulcer disease - takes losec dailyActive until about 1 mos. ago. Lost ~10 lbs. in the last 2-3 mos. Poor nutritional intake. Constipated. ++ ascites. Enlarged liver. Jaundiced.Arrived for day 1 of his 1st chemotherapy (etoposide & cisplatin) with c/o abdominal pain.Chemotherapy is for palliative intent.
4Mechanistic Approach to Pain SomaticSuperficialNOCICEPTIVE PAINDeepVisceralMIXEDCentralPeripheralNociceptive PainSomatic:superficial somatic - skin invasion or ulcerationdeep somatic – bone, - muscle, soft tissueVisceral:organsNEUROPATHIC PAINOthersAshby MA et al :
5Nociceptive: Somatic pain skin, muscle, connective tissue or bone dull, sharp, aching, stabbing, throbbing, or pressurewell-localizedusually associated with tissue damage as well as inflammatory processeseg. bone mets., pressure ulcer, infiltrated IV, incisionNociceptive: Visceral painorgans or tissuegnawing, cramping, aching, sharp, colicky, dull, or sharplocalized or referredeg. hepatomegaly, bladder spasmsCaused by direct stimulation of peripheral nociceptors
6Neuropathic painnerve involvement centrally or peripherallymay arise as a direct consequence of a lesion or disease affecting the somatosensory system (IASP 2007)sharp, tingling, burning, shooting, pins & needles, allodynia, burning, or lancinating
7Pain Assessment Findings P – Provocation & Palliation – lying, hiccups; certain positioning, heat, medication, relief of hiccups, relief of anxiety, sleep (BPI)Q – Quality of Pain - Classic neuropathic pain both anterior thigh areas with the usual burning, stinging, & sharp pain along with allodynia - possibly due to femoral nerve obstruction or paraneoplastic syndrome. (LANSS). Dull, achy pain in abdominal area - nociceptive pain (BPI)R – Region & Radiation - Pain moves from place to place; always persistent (BPI)S – Severity (on a 0-10 scale) - Pain score of 8-9 at rest and 10 + with activity (ESAS & BPI)T – Timing – constant unless using pain medication; time of day does not appear to influence pain experience (BPI)Feldt Tool – used to assess pain in non-verbal patientsReferenceFeldt, K.S. (2000). Checklist of nonverbal pain indicators. Pain Management Nursing, 1(1),Current medication – dosage/frequency, effects, side effects.A list of prescribed and over the counter medications is valuable to determine what is working, what didn’t work, etc.Ask about any alternative or complementary medications that the patient may have taken or may be taking.BPI – Brief Pain Inventory; LANSS-ESAS - Edmonton Symptom Assessment System
8Key Patient OutcomesMr. Pain verbalizes that pain is reduced or relieved to his satisfaction.Mr. Pain uses pharmacologic and non-pharmacologic interventions.Mr. Pain participates in activities of daily living with appropriate medications.
11Pharmacological: Opioids *Codeine*Hydrocodone**TramadolMorphineHydromorphoneOxycodoneMethadoneFentanylSufentanylLevorphanolMeperidineNaloxone/PentazocineMeperidine (demerol)Short durationLow analgesic potency p.o.High incidence of toxicity > 600mgs./24 hrs.Naloxone/Pentazocine (talwin)Limited oral bioavailabilityPsychomimetic s.e. highNever use with agonistsWeak OpioidsOpioids that can relieve mild to moderate pain, pain with a 4-6 scoreUsually mixed with other medicines such as acetaminophen or aspirin.Include hydrocodone, codeine, & tramadol.Eg. of weak opioids mixed with acetaminophyen or aspirin include Tylenol® with codeine, Fiorinal® with codeine, & Phenaphen® with codeine.Strong OpioidsOpioids that can relieve severe pain, pain with a score of greater than 7Other examples include fentanyl, methadone, levorphanol, hydromorphone, & oxycodone.Codeine combination products (>7 million prescriptions/yr)Oxycodone combination products (>1 million prescriptions/yr)
14The Analgesic Stepped Approach Increasing PainSevere PainModeratePainFentanylHydromorphoneMethadoneMorphineOxycodone(+/- nonopioid)(+/- adjuvants)MildPainCodeineOxycodoneTramadol(+/- nonopioid)(+/- adjuvants)The WHO Analgesic Ladder (Available at: recommends escalation from the use of non-opioid therapies, to opioids selective for moderate pain, and when pain persists, opioids for severe pain. Adjuvants are recommended as required. This three-step approach to the management of pain aims to provide “the right drug in the right dose at the right time”. Surgical intervention may also be necessary to provide further pain relief.AcetaminophenASANSAIDs/COXIBs(+/- adjuvants)World Health Organization. Cancer Pain Relief, with a Guide to OpioidAvailability. Geneva, Switzerland: WHO, 1996.Leppert W, Luczak J. The role of tramadol in cancer pain management – a review.Support Care Cancer 2005;13:5-17.
15Mr. Pain’s Story GP started him on hydromorphone contin ↓ in pain developed hives, urticaria & constipation
16Opioid Therapy: Getting Started Basic Considerations:Patient opioid exposure &experiencePatient fears (stigma)Caregiver & physician attitudes, preferences & biasesComplianceConvenienceCostSide effectsPharmaco-clinical Considerations:Patient sensitivities/allergiesAdministration & absorptionlimitationsMetabolism & clearanceOpioid profileFactors that we need to consider when initiating opioid therapyPatient exposure and experience-”I puked my guts out after they gave me morphine in the hospital after my surgery”Administration/Absorption-g-tubes,short gut syndromeMetabolism and Clearance-Renal dysfunctionOpioid Profile-Special properties. Methadone as Agonist and NMDA receptor antagonistFine PG. Journal of Pain, Aug. 2001
17Hydromorphone: Key Points ~ 5 x more potent than morphineFewer drug interactionsMay be used cautiously in renal failureVery soluble - up to 300 mg/mlAvailable in oral liquid, IR tablets, CR capsules, IR suppositories, & injectable form.Less sedation, less pruritis, less constipation & vomiting than morphineAvailable in oral liquid, IR tablets (2, 4, 8mg), CR capsules (3, 6, 12, 18, 24, & 30 mg), IR suppository, & injectable (1, 2, 4, 8mg/ml).Dilaudid (Hydromorphone)(Hydromorph Contin®)Sustained Release(Hydromorphone Injectable) Available 1, 2, 4, 8mgGiven Q4HAvailable in 3mg suppositoryAvailable 3, 6, 12, 24, 30mgGiven BID-TIDAvailable 2, 10, 50mg vialsPOSC butterflyHydromorphone PO or Injectable dosage may also be doubled at HS to avoid waking patient through the night.CADD (Computerized Ambulatory Drug Delivery System) or Syringe Driver may be used to deliver a continuous dose of injectable Hydromorphone.Hydromorphorone is approximately 5-6 times more potent than Morphine.Sustained release opioids (Contin) should NOT be doubled at HS.
18Pain & Substance Abuse Addiction Physical Dependence Tolerance both physical & psychological componentscontinuous craving & need for effects other than originally intendedresults in compulsive drug seeking behavioursthe 4 C’s: impaired control over drug use, compulsive use, craving, continued use despite harm (consequences)Physical Dependencepts. are physically acclimatized to the presence of the drugoccurs with long-term opioid usepts will experience withdrawal if drug is withheldif opiod withdrawn quickly then withdrawalPredictableToleranceGiven dose that relieved pain no longer produces the same degree and duration of reliefJCAHO pain standards at 1999withdrawal: restlessness, tremors, rhinorrheaNo predictable pattern of occurrence. In many ways, poorly understood.Risk of addiction is < 1% (Porter & Jick, 1980).Physical dependenceresults from continuous binding of exogenous opioids to opioid receptors.“a state of adaptation that often includes tolerance & is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, &/or administration of an antagonist. It is not the same thing as addiction. The symptoms of withdrawal include hypertension, nausea, vomiting, fever, shivering, diarrhea, and muscle aches. These symptoms can be minimized by slowly decreasing the dose of opioids. Weaning should be planned for any patient who has been taking opioids for more than one week.”(Taken from Accreditation Pain Standard: Making it Happen! Produced by The Canadian Pain Society)Addiction“is a primary, chronic, neurobiological disease, with genetic, psychosocial, and environmental factors influencing its development & manifestations. Characterized by the 4 C’s.”Pseudoaddiction“is a term which has been used to describe patient behaviours that may occur when pain is undertreated. Patients with unrelieved pain may become focused on obtaining medications, may “clock watch”, and may otherwise seem inappropriately “drug seeking.” Even such behaviours as illicit drug use and deception can occur in the patient’s efforts to obtain relief. Psuedoaddiction can be distinguished from true addiction in that the behaviors resolve when pain is effectively treated.”(Victoria House, 1998; Wickham, 2001)
19Screening for Addiction/Misuse Risk Previous history of substance abuse/addictionFamily history of drug abuse &/or addictionPrevious “chemical coping” with life stressesSignificant psychiatric historyPrevious high risk behaviours (esp. criminal activity)High risk home environment
21Opioid Therapy: Which Approach? Start with an IR opioid & titrate to effect When dose stable CR opioidfastest method for pain reliefStart with CR opioid & titrate dose q 1-3 days (or when side effects stable)for stable, chronic painStart with CR opioid baseline dose & use IR opioid to titrateonce weekly (may be as soon as q2-4 days in patients with cancer), add the total daily dose of IR to the CR dose and repeat weekly until dose stableThese 3 methods are your preferred methods for chronic pain patientsIf they add on an Oxy 10mg q12h = 1 Percocet q6h – which all MD’s prescribing percocet would doSo, why not start on a lower dose with the option of increasing the CR med??May need to titrate more rapidly in cancer patient.
22IR vs. CR Oral Opioids IR ORAL OPIOIDS CR ORAL OPIOIDS Onset of action 30 to 45 minutes~ 2 hoursOxycodone has 45 minute onsetPeak effect60 minutes- - -Serum half-life2 to 3 hoursDuration of action4 hours12 to 24 hoursCommentsQ6h dosing causes sub-therapeutic intervalsMonitor for end-of-dose failureNote: These studies were conducted in healthy volunteers, or post-op
23IR vs. CR Oral Opioids IR Oral Opioids CR Oral Opioids Advantages Quick onsetAllows for quick titration (as early as every 24 hours)Convenience and complianceUninterrupted sleepDisadvantagesFrequent dosingInterrupted sleepSlower titration (48 to 72 hours)Slower elimination in event of severe side effects
24Mr. Pain’s StoryGP switched to an equianalgesic dose of morphine i.e. 100mg BID.Uticaria disappeared. No change in hives or constipation.c/o mild, infrequent nausea.Started to become agitated & experienced hallucinations.
25Opioid Rotation Changing one opioid to another When: if pain is or has been relieved with original opioid, but toxicity limits further dose titrationApproximate dose ratio of two opioids required to produce a similar degree of analgesia“equianalgesic tables”
26Opioid Equianalgesic Doses OralParenteralmorphine30 mg q3-4h around the clock OR 60mg q3-4h single or prn dosing10 mg q3-4hcodeine130 mg q3-4h75 mg q3-4 hhydromorphone7.5 mg q3-4h1.5 mg q3-4hmeperidine300mg q 2-3h100 mg q3hoxycodone30mg q 3-4hN/A in CanadaCaution to docs switching from T3 to fentanyl to expect side effects such as sedation, in particular with patients that are opioid naïveNote that 7-10% of patients may not metabolize codeine and thus would then be considered opioid naïveThere are many equianalgesic table…..they are guidelinesMEDICATION P.O. DOSEMorphine 20 mgCodeine mgOxycodone mgHydromorphone 3-4 mg60-134mg oral morphine /day = 25 ug/hr td fentanyl1Jovey R. et al. Managing Pain. p. 1091 Health Cnada, 2009
27Choose another opioidCalculate the total dose of the analgesic over the past 24 hrs. If different routes have been used calculate separate totals.Calculate equivalent dose of new opioidAdjust starting dose of new opioid - consider ↓ initial dose by 25-50% if pain controlled by old opioid (no reduction if pain not controlled by old opioid) – accounts for incomplete cross-tolerance÷ the dose by the # of administration x/day to obtain the interval doseCalculate BTP pain medication dose.
28Morphine “Natural” drug derived from opium poppy. It’s the old standard NOT the gold standard.Very effective orally (first pass through liver).Duration of action for oral IR is ~ 4 hrs. & parenteral is ~ 3-4 hrs.Active metabolites may accumulate in renal insufficiency leading to toxicity; not recommended in renal failure.Fluctuating plasma levels can lead to variable efficacy & side effects. In the elderly bioavailability can be as low as 30%.More sedating & GI s.e. than the semi-synthetic opioids.More CNS effects in elderly (sedation, confusion, hallucinations)•Histamine release (pruritis)Injectable Available 10, 20, 30, 40mg scored tabs, Given Q1H PRN, BTP (breakthrough pain),Suppository available in 10 & 20mg strengthsAvailable in 15, 30, 60, 100, 200mg tabsGiven BID/TIDSuppository available in 30, 60, 100, 200mg strengthsAmpules 10, 15, 50mg vialsGiven Q4H, PO/elixir, PO/PR/gel capsSC butterflyMorphine dosage may be doubled at HS (up to an equivalency of 40 mg PO Morphine Q4H) in order to avoid waking patient at 0200.CADD (Computerized Ambulatory Drug Delivery System) or Syringe Driver may be used to deliver a continuous dose of injectable Morphine.IV Route of Administration is NOT recommended due to its short lived effect, and greater potential for toxicity.Epimorphine is calculated and administered by anesthestist via pump for intractable pain in lower part of body (especially bilateral or midline pain).Kadian(Sustained Release) Available 20, 50, 100mg capsules.Given q24h.The patient’s pain should be stabilized on immediate release Morphine first.The dose should be equivalent to the patient’s total 24hr Morphine dose.Administer the initial dose of Kadian along with the last dose of immediate release Morphine.Capsules may be opened and sprinkled on soft food~~not chewed or crushed.Cannot be given rectally.
30Codeine10% of the overall population lacks the enzyme (CYP450 2D6) required to metabolize codeine to active drug morphine2-5% of the population have relatively high amounts of the converting enzymeCeiling dose is 600 mg/dayMost constipating of all opioidsSome SSIs (Paxil, Prozac, Cymbalta) inhibit the conversion of codeine to morphineIR: 15mg, 30mg, 60mg tabletsCR: 50, 100, 150, 200mg tablets
31Oxycodone Hydrochloride Strong semisynthetic opioid; potency 2x > morphineConversion to oxymorphone may be inhibited by drugs such as fluoxetineCR form is OxyContin®.Dose initiation: 10mg q12h for opioid naïveNo pharmacological dose ceiling for pure opioid agonists.Can be used with close monitoring in renal failureSample titration schedule: 10, 20, 30, 40, 50, 60, 80, 100 mg q12h; can be titrated q24 hrs.μ& κ-opioidreceptor agonistOxycodone Side Effectsshallow breathing, slow heartbeatseizure (convulsions)cold, clammy skinconfusionsevere weakness or dizzinessfeeling light-headed, faintingnausea, vomiting, constipation, loss of appetitedizziness, headache, tired feelingdry mouth, sweating, itchingIR: 5, 10, 15mg tabletsCR: 10, 20, 40, 80mgJovey, R. et al Managing Pain , Pg 96
32Methadone Powder, capsule, liquid, suppositories Long half-life (q8h). Half-life variable making it unpredictable with repeated doses sudden severe toxicity.Variable equianalgesic dose to other opioidsIndividual titration with close monitoring is extremely importantSpecial authorization from Health CanadaMany drug interactions with CYP450 3A4Less constipating; does not cause metabolite accumulation; less expensiveA good option in neuropathic painMethadone, a synthetic opioid has some unique properties. It is the only truly long-acting opioid available (others depend on a controlled release mechanism).Methadone can be dosed once daily to prevent opioid withdrawal in opioid addicted people but is usually dosed q6-8h for pain. Extra caution is required when switching from another opioid to methadone due to a variable equianalgesic ratio. Naïve patients should be started on a small 5mg test dose before titrating. Use the “rules of 3” for safe titration: Never repeat a dose within 3 hours of a previous one, and never titrate the dose sooner than every 3 days. May cause ventricular arrhythmias (Torsades) in patients on higher doses who also have low Mg, K or Ca. It is metabolized by CYP450 3A4 enzyme. Many commonly prescribed drugs (Macrolides, Fluoroquinolones) may interfere with methadone metabolism and cause toxicity.See slide #83 for web site of drug interactions
33Cytochrome P450 Drug Interaction Table University of IndianaDepartment of MedicineThis is an excellent website, updated regularly, which lists all of the major Cytochrome P450 drug interactions. Most opioids are metabolized by 2D6. Fentanyl and methadone are metabolized by 3A4.
34FentanylUse if difficulty with oral meds; compliance issue; intractable side-effects25ug. of Fentanyl range is mg oral morphine equivalents160mg of morphine or equivalent before switching to the 25ug. patch; 45mg if 12.5ug. patch.When applying 1st patch continue with other pain medication x 24 hrs.Rate of absorption can be affected by: fever, soap, oils, alcohol, shaving skinDuragesic/Fentanyl Patch Available in 25,50,75,100 µg/hrApplied q3days Topically on dry non hairy area back,chestupper arms When applying the initial patch the patient will require additional pain medication during the first 24 hours, as it is a slow released product.To be used in combination with short acting narcotics, such asMorphine for breakthrough painShould not be used in conjunction with sustained released opioidsRate of absorption may be affected by:·Fever·Soap·Oils·Lotions·Alcohol·Shaving skinIf patch must be applied to a hairy area, clip hair with scissors do not shave. Apply patch and hold in place for 30 secIf patch falls off and is not damaged may reapply firmly by applying micropore tape OR a new patch may be appliedStore at room temperatureWhen removing, fold sticky sides together and flush down toiletRotate patch sitesDuragesic patch: 12.5, 25, 50, 75, 100 ug.1Health Canada, January 2009
35Sufentanil (sufenta)Approximately 5 to 10 times more potent than fentanylRelieves pain by stimulating opiate receptors in CNS25-50 mcg SL/buccal.Good choice for use just before activity.Pt. teaching re: taking it.Possible side effects: respiratory changes, heart rhythm irregularity, peripheral vasodilation (blood pressure changes), inhibition of intestinal peristalsis (constipation), sphincter of Oddi spasm, & nausea/vomiting
36Tylenol # 3 300mg acetaminophen + 30mg of codeine in each tablet 12 x Tylenol #3 (usual daily dose) = 3.6g total daily dose of acetaminophen & 360mg of codeine – this exceeds what is safely recommended for chronic use in healthy patientsTylenol # 3 also contains caffeine.
37Acetaminophen*- Suggested Dose Ceilings 4 gm/day > 10 days in healthy, well-nourished patients – short-term use in healthy patients3.2 gm / day for chronic use in healthy patients2.6 gm / day chronically in at risk patients*Daily alcohol consumption, warfarin, fasting, a low protein diet, cardiac or renal disease increase the risk of hepatotoxicityThere is no actual published evidence for the commonly recommended dose ceiling of 4 gm / day of acetaminophen. Ken Latta, an academic pharmacist from Duke University has been collecting the literature on acetaminophen toxicity and has developed the above guidelines for the teaching hospitals affiliated with Duke.The risk of hepatotoxicity increases with 3 or more drinks of alcohol per day. (U.S. FDA Jan, 2004)Zimmerman & Maddry, 1995Seeff et al., 1986Swarm et al., 2001Bromer MQ, Black M. Acetaminophen hepatotoxicity. Clin Liver Dis2003;7:351-67Latta, 2000Garcia Rodriguez, Arthritis Res 2001; Curhan 2002Watkins et al., 2006.Latta, 2000
38TramadolAn opioid analgesic with a dual mechanism of action (weak affinity to the Mu receptor + inhibits the reuptake of serotonin & norepinephrine)Recommended for the tx. of moderate - moderately severe pain.CR tramadol can be initiated in opioid naïve at lowest doseLess constipating then codeineMaximum 400mg/dayTramadol Side Effectsseizure (convulsions)a red, blistering, peeling skin rashshallow breathing, weak pulsedizziness, drowsiness, weaknessnausea, vomiting, constipation, loss of appetiteblurred visionflushing (redness, warmth, or tingly feeling)sleep problems (insomnia)
39Tramadol Dosing Immediate release (Tramacet) One tablet is 37.5mg Tramadol HCL/ 325mg of acetaminophenMaximum dose is 8 tablets per 24hoursBeneficial for acute painExtended release (Zytram XL1, Ralivia, Tridural)Doses 100mg, 150mg, 200mg, 300mg, and 400mgIf on IR tramadol calculate 24 hr. dose & initiate total daily dose rounded down to nearest 100 mg, titrate up to max. of 400mg/day
40What is the appropriate intervention for Pain’s opioid therapy? Discontinue morphine and initiate tramadol.Switch from MS Contin to OxyContinAdminister MS Contin once a day, rather than every 12 hoursChange dose of morphine and add a co-analgesic.Answer: Switch from MS Contin to oxycontinTramadolImmediate release (IR)Start at 25mg./day, titrate slowly up to mg q4-6 hrs (max. 400mg/day)Rapid analgesic onset: start at mg q4-6 hrs (max. 400mg/day)Extended releaseIf not on IR tramadol start at 100mg/day; titrate up to max. 300mg/dayIf on IR tramadol calculate 24 hr. dose & initiate total daily dose rounded down to nearest 100 mg, titrate up to max. of 300mg/day
42Breakthrough PainAlways have BTP ordered: ensure it is adjusted if regular dose is adjusted.30-50% of regular dose q4hrs. (you may want to use 1/10 to 1/6 of the total daily dose usually q1hr.)Same drug is usually used; may use other drugs.>/= 3 doses BTP/24 hours add to regular doseIf pain is not improved after 1-2 BTP increments re-evaluate cause of pain.
43Based on Mr. Pain’s description of his pain, would you consider a co-analgesic?
44What co-analgesic would you add to Mr. Pain’s pain management plan? BaclofenNeurontinZoledronic acidNortiptyline
45What was Prescribed? Neurontin (gabapentin) 100mg BID x 2 days 100mg TID x 2 days200mg TID dailyBaclofen 5mg q8hrSenokot-S 2 tabs. at hs
46Which of the following side effects will you need to monitor when neurontin is initiated? Constipation, nausea, itching, tremors, and hallucinationsSedation, dizziness, nausea, confusion, and lower extremity edemaAtaxia, nausea, alterations in liver enzymes, and weight gainAtaxia, nausea, vomiting, and diarrheaCorrect response: Sedation, dizziness, nausea, confusion, and lower extremity edema
47NeurontinProven indications: postherpetic neuralgia (PHN) & diabetic neuropathyWidely considered to be first-line (co-analgesic) agent for neuropathic pain despite off label statusFewest drug interactions of all AEDsCommon adverse effects: somnolence, dizziness, fatigue, ataxia, S & S of CNS depressionReferences:Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of pain neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 1998;280:Rowbotham M, Harden N, Stacey B, et al. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 1998;280:
48Neurontinmg mg qhs; PHN initiate at 300mg day 1, 600mg day 2 in divided dose, 900mg day 3 in divided dose, & titrated further as needed up to mgSupplied in 100mg, 300mg, 400mg, 600mg, 800mg capsulesDose reduction needed in renal compromiseMorphine increases the neurontin concentration in the blood
50Antiepileptic Drugs Neurontin Pregablin (lyrica) Lamotrigine Well-tolerated with proven efficacy in neuropathic pain caused by neurotoxic anti-retroviral therapy in HIV-positive patientsCarbamazepine mg BIDValproate 250mg daily to TIDReason for analgesic efficacy unclearReduce membrane excitabilitySuppress abnormal discharges in pathologically-altered neuronsAffects sodium channelsIndications: acute and chronic neuropathic pain from peripheral nerve syndromesTrigeminal neuralgiaDiabetic neuropathyPostherpetic neuralgiaEfficacy with both lancinating and burning painReferences:Simpson DM, et al. Lamotrigine for HIV-associated painful sensory neuropathies: a placebo-controlled trial. Neurology 2003;60:Eisenberg E, et al. Lamotrigine reduces painful diabetic neuropathy: a randomized, controlled study. Neurology 2001;57:
51Pregablin (Lyrica) Indicated for the management of: Side Effects: Neuropathic pain associated with diabetic peripheral neuropathyPostherpetic neuralgia PHN)Side Effects:dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, constipation, euphoric mood, balance disorder, increased appetite, and thinking abnormal (primarily difficulty with concentration/attention)References:Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of pain neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 1998;280:Rowbotham M, Harden N, Stacey B, et al. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 1998;280:
52Pregablin (Lyrica) Available: 25mg, 50mg, 75mg,150mg, 300mg Recommended dose/day: 150mg, 300mg, 600mgPHN patients who tolerate LYRICA may benefit from up to 600 mg/day after 2 to 4 weeks of treatment with 300 mg/dayMay take up to a week to receive benefit.May exacerbate the effects of oxycodone, lorazepam, or ethanol on cognitive & gross motor functioning.Discontinue gradually over a minimum of 1 week.
53Cyclic Antidepressants AmitriptylineBest-established efficacy; most widely used for painHighest anticholinergic s.e. profile of all cyclic antidepressantsCommon s.e.: sedation, constipation, dry mouth, blurred vision, urinary retention10-25mg mg qhsNortriptylineLess sedation & anticholinergic side effects than amitriptylineCommon adverse effects include sedation, dry mouth, constipation10-25mg qhsDesipramineTolerability & efficacy similar to that of nortriptylineLess anticholinergic side effects than amitriptyline25mg qhsAvoid cyclic antidepressants if QTc > 440 msec or if AV block
54Non-Opioid Analgesics: Acetaminophen Used for mild-moderate nociceptive painDose ceiling2 key side effects: renal toxicity & risk for hepatotoxicityUsual dose: 325mg 1-2 tabs q4-6hAcetaminophen is thought to act on the recently discovered COX-3 enzyme. It has been used over the counter for decades for the treatment of mild to moderate nociceptive pain. There is evidence for effectiveness in post operative pain. The maximum recommended daily dosage of acetaminophen is 4000 mg. Dosages in excess of 4000 mg per day risk hepatotoxicity by exceeding the ability of the liver to glucuronidate toxic metabolites. It is recommended that the daily dosage of acetaminophen be reduced to less than 3000 mg per day in patients with hepatic diseases such as hepatitis and cirrhosis.There is no actual published evidence for the commonly recommended dose ceiling of 4 gm / day of acetaminophen. Ken Latta, an academic pharmacist from Duke University has been collecting the literature on acetaminophen toxicity and has developed the above guidelines for the teaching hospitals affiliated with Duke.The risk of hepatotoxicity increases with 3 or more drinks of alcohol per day. (U.S. FDA Jan, 2004)-Evidence in postop pain: A single dose of 1000 mg had an NNT of 3.8 ( ) for at least 50% pain relief over 4-6 hours in patients with moderate or severe pain (a single dose of mg had an NNT of 4.6)Case, 2003; Zimmerman, 1995, 2000; Bromer, 2003; Perneger, 1994; Garcia Rodriguez, 2001; FDA Sept. 2002; Health Canada Feb. 2003; Curhan
55NSAIDS # & diversity have increased over the past 20 yrs. Evidence detailing effectiveness is contradictory – COX I & COX IIAnalgesic & anti-inflammatory effectsRoutes: Oral preferred, IV faster onsetCeiling DoseMonotherapy for mild-moderate painCo-analgesic for severe painEffective in inflammatory arthritisLittle long-term evidence in osteoarthritisFunctions of prostaglandins:Protect gastric mucosaSupport renal and platelet functionInflammation & pain responsePros and Cons of NSAIDsOptimal analgesia may require COX I and COX II1Increased risk of CV events with COXIBs2, 3,4COXIBs block prostacyclen but not thromboxane5COXIBs have no antiplatelet activity and do not substitute for ASADelayed healing of fractures in animals61. McCormack, 2002; 2. Mukheriee D. Jama 2001; 3. Howard PA, Jam Coll Cardiol, 2004;4. Topol E, NEJM Marcus A.J. NEJM 2002; 6. Simon AM. JBMR 2002Action: Both traditional COX-1 & -2 & selective COX-2 inhibit prostaglandin synthesis at peripheral sites of inflammation; central effect poorly understoodIbuprofen 400mg NNT of 2.4 ( )ASA 650 mg: NNT pf 4.4 ( )Diclofenac 50mg: NNT of 2.3 ( )Naproxen 550mg: NNT of 2.6( )NNT of at least 50% pain relief over 4-6hrs following single dose.Non-steroidal anti-inflammatory drugs can be very effective in the management of nociceptive pain association with tissue damage (including surgical pain) as well as inflammation.Reference for Ibuprofen: Barden J, Edwards JE, Collins SL, McQuay HJ, Moore RA. Single dose ibuprofen for postoperative pain. The Cochrane Library, Update Software, Oxford, 2002.Reference for ASA: Edwards JE, Oldman A, Smith L, Collins SL, Carroll D, Wiffen P, McQuay HJ, Moore RA. Single dose Aspirin in acute pain. The Cochrane Library, Update Software, Oxford, 2000 (updated with no additional results 2002).Reference for diclofenac: Barden J, Edwards JE, Collins SL, McQuay HJ, Moore RA. Single dose diclofenac for postoperative pain. The Cochrane Library, Update Software, Oxford, 2002.Reference for naproxen: Mason L, Edwards, JE, Moore RA, McQuay HJ. Single dose naproxen for acute postoperative pain: a quantitative systematic review. BMC Anesthesiology 2003;3:4A systematic review found that in most cases, the oral route of administration provides equivalent analgesia with fewer adverse effects compared to rectal and parenteral routes. Reference: Tramer M, Williams J, Carroll D, Wiffen PH, McQuay HJ, and Moore RA. Comparing analgesic efficacy of non-steroidal anti-inflammatory drugs given by different routes for acute and chronic pain. Acta Anaestheiologica Scandinavica 1998;42:71-79.
56NSAIDs/COXIBsIncrease risk of exacerbation of underlying renal insufficiencyIncrease risk of fluid retentionIncrease risk of cardiovascular complicationsIncrease risk of GI bleeds (especially NSAIDs in patients requiring concomitant ASA for cardiovascular prophylaxis)
57NSAIDs Side effects Contraindications GI distress Bleeding 2° to platelet dysfunctionRenal failureBronchoconstriction? Delay in bone healing
58Which one?Ketoprofen (Orudis) – mg daily (RA & OA); 50mg TID-QID (menstrual cramps & mild-to-moderate pain)Indomethacin (Indocid) – 25mg BID - TIDIbuprofen (Motrin) – mg TIDToradol (Ketorolac) – 10mg q4-6hrNaproxen (Naprosyn) – mg BIDDiclofenac (Voltaren) – 25-50mg TID or 75mg SR daily (maximum dose 150mg)ASA – mg QID/q4hrRofecoxib (Vioxx) - Sept removed from marketCelecoxib (Celebrex) – mgQD-BIDThe problem with ASA must be underscored. In both the CLASS and VIGOR trials, concomitant use of ASA (as much as 325 mg per day) negates the GI protective effects of COXIBs. Given the widespread use of low-dose ASA, one has to wonder just how much safety benefit patients who use COXIBs actually obtain. For a good discussion on the subject, see: *McQuay HJ, Moore RA. Side effects of COX-2 inhibitors and other NSAIDs. In Proceedings of the 10th World Congress on Pain, Jonathon O. Dostrovsky, Daniel B. Carr, Martin Koltzenburg Eds. Progress in Pain Research and Management Volume 24, pp , IASP Press, Seattle.**Chan FKL, Hung LCT, Suen BY, et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med 2002;347:Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ 2000;321:COXIBs = NSAIDs10-17% of patients have increased BP1Acute and chronic renal toxicity2Double the risk of hospitalization for CHF3Delayed gestationIncreased miscarriage risk4No evidence in neuropathic pain1. Cheng HF. Hypertension, 2004; 2. DeMaria AN. JPSM 2003; 3. Garcia-Rodriguez LA. Epidemiology 2003; 4. Li DK. BMJ 2003*McQuay HJ, Moore RA.. In Proceedings of the 10th World Congress on Pain.Jonathon O. et al. Progress in Pain Research and Management Volume 24, pp , IASP Press, Seattle.**Chan FKL, et al. N Engl J Med 2002;347:*Taking ASA nullifies the GI protective effect of COXIBs
59Toradol Suggested for moderate pain. Recommended as an alternative to low-dose opioids.Suggested to limit oral use x 7 days or parenteral to 2 days.Major s.e. are GI; need something for GI side-effect prevention.
60Cytoprotective Agents Sucralfate (1gm Qid)misoprostol (200ug Qid) * not best choiceH2 receptor antagonists eg. Cimetidine, ranitidineOmperazole 20-40mg/day
61Is an NSAID a good choice for Mr. Pain? History of ulcer complicationsMultiple NSAIDSHigh-dose NSAIDSConcomitant anticoagulant useAge >/= 60yrs.Concomitant corticosteroid useHistory of cardiovascular disease
62Other Medications for Pain Muscle relaxantsCyclobenzaprine, BaclofenLocal anesthetic congenersIV Lidocaine, oral MexiletineNMDA (N-methyl D-aspartate) blockersDextromethorphine, ketamineAlpha-2 agonistsClonidine, TizanidineBotulinum ToxinVan Tulder MW, Touray T, Furlan AD, Solway S, Bouter LM. Muscle relaxants for nonspecific low back pain: a systematic review within the framework of the cochrane collaboration.Spine Sep 1;28(17): Mao J, Chen LL. Systemic lidocaine for neuropathic pain relief. Pain Jul;87(1):7-17. Kalso E, Tramer MR, McQuay HJ, Moore RA. Systemic local-anaesthetic-type drugs in chronic pain: a systematic review. Eur J Pain Mar;2(1): Smith HS, Barton AE. Tizanidine in the management of spasticity and musculoskeletal complaints in the palliative care population. Am J Hosp Palliat Care Jan-Feb;17(1):50-8. Review. Lang A.M. Botulinum toxin type A therapy in chronic pain disorders. Arch Phys Med Rehabil Mar;84(3 Suppl 1):S69-73; quiz S74-5. Review.
63Mr. Pain has already experienced uticaria, rash, constipation, agitation, & hallucinations from his opioid therapy. What other side effects might you anticipate with ongoing opioid therapy?Discuss the acute side effects with patients before prescribing. They are more likely to persist if they know that the acute side effects are temporary.Be proactive with side effects
64Side Effects of Opioids COMMONLESS COMMONRARESide effectNausea and vomitingConstipationSedation and drowsinessConfusionMyoclonusDry mouthUrinary retentionSweatsGE refluxPruritusRespiratory depression (very rare in properly titrated patients)Note: Long term side effects of chronic use covered in later section.Respiratory depression issue in opioid naïve patients given improper doses, i.e. medication errors. Case of girl at Sick Kids in Toronto receiving 10 mg IV instead of 1 mg IV precipitating respiratory arrest and death.
65Treatment of Common Opioid Side Effects Nausea and vomitingOndansetron 8mg q8hr prnHaloperidol mg od-tidPhenothiazine 5-10 mg PO q4-6h prnDimenhydrinate often too sedatingIf motility is an issueMetoclopramide mg qidConstipationUse dietary measures first (bran, flax, prunes)Osmotics-MOM, lactuloseStool softeners - docusateStimulants-senna, bisacodylSuppositories-dulcolaxEnemasConstipation-highlight differences in management between cancer and non-cancer population (ie more aggressive use of bowel stimulants in cancer patients)Lack evidence to support the use of docusate in relieving constipationSee reference section for treatment of side effects documentDiscuss pros and cons of each antiemetic. Use drugs of choice from your practice
66Opioid NeurotoxicityPresents as agitation, confusion, myoclonus, hallucinations & rarely seizuresPossible precipitantsInfection/SepsisDehydrationDecreased renal clearanceRapid dose escalationManagement: ↓ dose or hold medication until sensorium clears, Opioid rotation, Consider hydration with both options
67Mr. Pain’s StoryPresented for his 2nd chemotherapy tx. with well controlled pain.Reported taking fewer BTP medication, once or twice q3-4 days.Oncologist decreased his pain medication.At this point you need to determine what is happening…..time to reassess, readdressDetermine what is happening, treat the underlying disease.It is a common occurrence that patients spontaneously discontinue their own meds-sometimes up to 1/3 of themDecreasing Dose or Discontinuing OpioidsPossible IndicationsDramatic decrease in painIncrease in side effects despite stable dosageResolution of underlying problemActive addictionIf patient wants to discontinue
68Opioid Dose ReductionCareful reduction to decrease opioid toxicity – monitor pain controlDose reduction may include the concurrent addition of adjuvant analgesicsTapering ScheduleFirst 48 hours: decrease daily dose of opioid by 50% inSecond 48 hours: *decrease daily dose by 25% (assuming no increase in pain)Third 48 hours: *decrease daily dose by 25%May prescribe IR opioids to minimize interdose pain or withdrawal symptomsRemember this is a non fatal withdrawalIn tools section there is a two page document title “managing opioid withdrawal” that can be utilized…….this is an alternate and slower method than the one mentioned above.10% reduction per day, per week, per month, etc.Slow dose reduction at the end of the wean.Use Clonidine for withdrawal symptoms.Use Clonazepam for withdrawal symptoms.Methadone withdrawal symptoms may persist after end of withdrawal.
69Putting it AltogetherSusan has been receiving hydromorphone 2 mg s/c. She is now able to tolerate oral medication. The best option for the oral dose would be:A. 1 mgB. 2 mgC. 4 mgD. 8 mg
70Putting it Altogether A. 15 mg BID B. 30 mg BID C. 45 mg BID Jane has been taking 10 mg. of morphine by mouth q4hr with good relief. A decision has been made to switch her to a sustained release morphine. The starting dose should be:A. 15 mg BIDB. 30 mg BIDC. 45 mg BIDD. 60 mg BID
71Take Home Pearls Assessment is key. Goal is to reduce pain to an acceptable level.Involve the patient in goal setting & negotiating analgesic strategies.Do not delay treating pain – avoid chronic pain.A multi-modal approach is recommended (pharm & non-pharm).Prevention is better than treatment – give meds regularly.Use least invasive route possible & avoid IM injections.Anticipate & manage side effectsIf there is a question with regard to “no ceiling dose” how would you respond?no pharmacological ceiling doseLimitations may be based on side effectsThe key is to document well the need/outcome of a high doseconsider dosing as dynamic not static** If the MD has a “personal” dose ceiling that the patient has reached and the patient remains less than well controlled, this may be an indication for a consult**