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How to Keep The Patient in Pain Sleeping at Night (and you awake in the morning ) Barry Bass University Center for Pain Medicine UTHSC, Houston Pain Management For Objectives • • • • To identify types of pain To clarify principles of pain assessment To clarify the basic principles of prescribing To discuss the basic pharmacological principles of opioid and adjuvants used in pain management • To discuss the practical application of drugs used in analgesic therapy with emphasis on patient safety , risk benefit comparisons and cost containment Acute Pain An unpleasant reaction/sensation secondary to tissue damage Acute Pain • • • • • Corresponds to the degree of injury Is self limiting Serves a purpose Responds to conventional therapy Attracts sympathy and concern from family and caregivers • Minimal affective response • Treatment is cost effective • Good outcomes Chronic Pain • • • • • • • Outlasts the initial injury Subjective exceeds the objective findings Poor response to conventional therapy Serves no beneficial purpose Poor response from family and care givers Cost ineffective therapy Accompanied by major psycho-social comorbidity • High incidence of substance abuse Definition of Persistent (Chronic) Pain • Any pain that – Persists beyond the expected time after a physical or emotional injury – Subjective complaints are magnified – Pain is out of proportion to clinical signs – Is accompanied by severe psycho-social issues – Responds poorly to conventional therapy Persistent Pain PAIN SUFFERING DEPRESSION LOSS OF FUNCTION DRUG ABUSE FINANCIAL LOSS DOMESTIC DISRUPTION Scope of The Problem • • • • • • One in four Americans has persistent pain Commonest reason for PCP office visits Over 50% of Cancer patients have severe pain 60% of the elderly have persistent pain Commonest cause of disability Health care costs related to persistent pain is $100 billion and rising rapidly • Lost work hours secondary to persistent pain can double the costs • Rising rate of substance abuse rate-item The Good ACUTE PAIN tg/stores/d The Bad cavorite-lis n -fGET tg/stores/d communit rate-item cust-rec just-say-no true m/justsay Persistent nociceptive Pain The Ugly Neuropathic Pain communit Who Gets Persistent Pain ? • Systemic disease – – – – – – – Diabetes mellitus hypothyroidism HIV/AIDS Hepatitis C Malignancy Neurological disease….ALS, MS Rheumatoid related syndromes • Obesity • Psychiatric co-morbidity Types of Persistent Pain • Nociceptive – – – – Musculo skeletal Joint Ligamentous Visceral • Neuropathic – Central – Somatic – Sympathetic • Psychogenic • Mixed Neuropathic Pain Pain secondary to biochemical and structural changes within the central and peripheral nervous system. Pain Transduction Pain conduction Pain processing Pain perception Pain expression Pain Assessment • The pain itself – – – – Intensity Radiation Type Relieving exacerbating factors • Functional assessment • Behavioral assessment • Medication usage Pain Assessment • Characterize the pain • Characterize the disease, relationship between pain and disease and potentially treatable etiologies • Clarify syndromes and infer pathophysiology • Determine need for urgent therapy • Identify other needs • Develop a therapeutic strategy Pain Intensity Rating Scales • Visual Analogue Scale (VAS) No pain ----------------------------------- Worst pain • Numerical Rating Scale 0 ------------------------------------------- 10 Worst pain imaginable No pain • Categorical Scale None (0) Mild (1 – 4) (Cleeland, 1991; Jacox et al, 1994) Moderate (5 – 6) Severe (7 – 10) Red Flags in Pain Assessment • • • • • • • • • • • Poor function Pain always a 10 out of 10 Behavioral co morbidity Obsession with drugs Altercations with staff Focus on particular medications Multiple admissions for pain therapy Frequent ER visits Illegal drug usage Alcohol and tobacco abuse Poor motivation Guidelines in Pain Therapy • • • • • • • • Assess the pain frequently Pain assessment must be dynamic and not static Be pre-emptive Be mechanistic Use around the clock therapy (ATC) Treat and assess breakthrough pain aggressively Where possible use oral route Consider age, previous drug usage, hepato- renal function • Monitor for abuse • Monitor and treat side effects • Be cost effective Neuro -Physiology of Pain TRANSDUCTION CONDUCTION PERCEPTION CONDUCTION Descending Modulation EXPRESSION Mechanistic Approach To Therapy Modify expression..anxiolytics Decrease inflammatory response. NSAIDS, local anesthetics, steroids Increase inhibition.. Amitryptiline venlafaxine, clonidine Prevent centralization Decrease conduction gabapentin, carbamazepine,local anesthetics, opioids cox2,opioids, ketamine,alpha 2 agonists. Mechanistic Approach to Drug Therapy in Persistent Pain • • • • • • • Decrease peripheral sensitization Delay or block conduction Suppress automaticity Inhibit central amplification Increase descending inhibition Modify central perception Modify expression The Opioids Cancer Pain……… Palliation Non Malignant Pain………Rehabilitation Efficacy of Opioids in Persistent Pain States • Nociceptive pain • Visceral pain • Neuropathic pain WHO Analgesic “Ladder” for Cancer Pain Freedom from Pain Proposed 4th Step Intrathecal Opioid Delivery Pain persisting or increasing Step 3 Opioid for moderate to severe pain ± Nonopioid ± Adjuvant WHO 3-Step Analgesic Ladder Pain persisting or increasing Step 2 Opioid for mild to moderate pain ± Nonopioid ± Adjuvant Pain persisting or increasing Step 1 ± Nonopioid ± Adjuvant Pain Deer T, Winkelmuller W, Erdine S, et al. Intrathecal therapy for cancer and nonmalignant pain: patient selection and patient management. Neuromodulation 1999;2:55-66. Breakthrough Pain • End of dose • Pathological • Incidental • Tolerance Principles of Breakthrough Pain Therapy • • • • • • Should not exceed 25% of the daily dose Should stay within the therapeutic window Should have minimal side effects Should not be randomly escalated If needed more than 4 hrly. Increase ATC. Assess for abuse vs tolerance Opioids Used for Pain Management • • • • • • • • • • • Morphine Sulphate Hydromorphone (Dilaudid) Strong Opioids Demerol Fentanyl Methadone Buprenorphine Partial agonists Pentazocine Oxycodone (Roxycodone, Tylox, Percocet) Weak Hydrocodone (vicodin, lortab, Norco) Propxyphene ( Darvon, Darvocet) opioids Codeine Routes of Administration • Intravenous – PRN nurse administered – PCA • Oral – PRN – Around the clock • • • • Transdermal Rectal Transmucosal……oral or nasal Neuraxial – Intrathecal – epidural The PRN Scenario 20 minutes The PCA PHARMACOKINETIC GOALS SIDE EFECTS NO PAIN PAIN HOURS Indications for PCA • Moderate to severe pain requiring opioids • Pain anticipated to last >10-12 hours • Patients willing to control their analgesia • Patient able to understand PCA • Oral route is not appropriate • Procedural pain Choice of Opioid in PCA • Depends on: – – – – – – Allergies Renal function Liver function History of abuse Individual response Previous surgical history • Cost consideration Loading Dose • Morphine 50 mg/kg q 10 minutes – 80 kg = 50 X 80 = 4,000 mg = 4 mg • Fentanyl 0.5 mg/kg q 5 minutes – 80 kg = 0.5 X 80 = 40 mg • Hydromorphone 10 mg/kg q 10 minutes – 80 kg = 10 X 80 = 800 mg = 0.8 mg Maintenance Dose • Morphine 25 mg/kg q 10 minutes – 80 kg = 25 X 80 = 2,000 mg = 2 mg • Fentanyl 0.25 mg/kg q 5 minutes – 80 kg = 0.25 X 80 = 20 mg • Hydromorphone 5 mg/kg q 10 minutes – 80 kg = 5 X 80 = 400 mg = 0.4 mg III. PCA • Morphine 1 mg / ml (5 mg/ml) • Fentanyl 10 mg/ml (50 mg/ml) • Hydromorphone 0.2 mg/ml (1 mg/ml and 5 mg/ml) • Meperidine 10 mg/ml The Demand Dose with PCA • <0.5 mg MS is associated with poor analgesia • >2 mg MS associated with over sedation • Excessive demands – – – – – Poor pain relief or change in medical status Pump failure Patient confusion…………..elderly Family interference………..elderly and children Inappropriate patient use…….abuse • Adjust bolus dose if poor pain relief with >4 demands per hour • With line occlusion alarm set for 3 failed demands The Lockout Interval • Time interval to assure full effect and to minimize sedation…..a safety feature • Too long a lockout will reduce the effectiveness of the PCA • Too short a lockout will increase risk of sedation • Lockout of 7 -11 minutes for morphine • Lockout of 6-10 minutes for hydromorphone • Lockout 5-8 minutes for fentanyl Ginsberg. Pain.1995:62:95 The Lockout Interval • Time interval to assure full effect and to minimize sedation…..a safety feature • Too long a lockout will reduce the effectiveness of the PCA • Too short a lockout will increase risk of sedation • Lockout of 7 -11 minutes for morphine • Lockout of 6-10 minutes for hydromorphone • Lockout 5-8 minutes for fentanyl Ginsberg. Pain.1995:62:95 Basal Infusions with PCA • Infusion will continue regardless of sedation level • Responsible for most instances of oversedation ..1-3% cf. <0.5% with demand • Removes the feed back loop • Does not offer improved pain relief • Does not offer improved sleep • No difference in number of demands • Does increase total opioid delivered • Increased risk of programming errors • Only to be used if patient is opioid tolerant with knowledge of daily requirements Rudolph.Anes.Analg.1999.89:1226 Inadequate Analgesia with PCA • Check – – – – Demands The machine The IV The lesion being treated • Abuse potential Inadequate Analgesia with PCA • • • • • • • Increase the bolus dose Decrease the lockout Educate the patient Start basal infusion Change the route Change the opioid Add an adjuvant – Antidepressant – Anticonvulsant – Anti inflammatory • Treat the lesion Extreme Caution with Basal Infusion • • • • • • Children Elderly OSA disease Morbidly obese Hypovolemia Renal impairment……….when using morphine and Demerol. • Inexperienced nursing staff • With concurrent epidural infusion Etches. Can. J. Anes. 1994.41:125 Continuous Infusion • Not routine • Start an infusion if: – Inadequate analgesia over >6 hours – Opioid-tolerant patient • Infusion rate based on hourly use over previous 6 hours – Opioid-naïve 25-50% of hourly requirement – Opioid-tolerant 50-75% of hourly requirement PCA Dosing in Children Lockout 6-10 minutes Drug/Potency Morphine/1 Hydromorphone (Dilaudid/5 Fentanyl/20 PCA dose Basal 10-20mcg/kilo 5-30mcg/kilo/hr 2-6mcg/kilo 1-6mcg/kilo/hr 0.5-1mcg/kilo 0.25mcg/kilo/hr Used in children over the age of 6 years Patient • • • • • • • • Education PCA Assess patient competency Allay fears regarding addiction Press the button before pain is intolerable Family not to press the button Nurses not to press button Do not clock watch Hit button whenever you want Reassure fears of sedation Meperidine…….Demerol • • • • • • • • Short acting Toxic metabolites Metabolites with long half life >12 hrs Increased risks in renal failure High addiction potential Expensive High incidence of caregiver diversion Gradually being phased out Normeperidine Toxicity Asymptomatic Shaky Feelings Tremors/ Twitches Myoclonus/ Grand mal 19 20 9/9 8/2 Days of administration 1.2 (0.1) 1-2 8.0 (1.2) (1-22) 6.7 (1.9) (1-30) 5.9 (1.0) (3-10) Rate of admin. (mg/day) 170 (18) (75-380) 350 (52) (59-1080) 370 (66) (46-1100) 420 (37) (260-540) Patient Group N Kaiko RF et al, Ann Neurol 1983;13(2):180-5 Equianalgesic Dosing Drug Oral po Morphine 30 /1 200/1 Oral SR durn 3-5 10 2-3 100 .5-1 2-4/2 3-4 10/1 oxycodone 10/1 20/2 methadone 3-4 3-4 demerol fentanyl dilaudid 30-60 IV hydrocodone 10 6-8 im peak Half life 2-3 unpred 0.1 30 1 45 0.5 30 2-3 2 mins 4-5 3-4 8 1 15-30 Opioid Equivalencies/ Conversions Drug PARENTERAL oral factor* MSO4 10 mg 30mg 3 Oxycodone -------- 15-20 --- Methadone 10MG 20mg 2 Dilaudid 1.5 mg 7.5 mg 5 codeine 130 mg hydrocodone ------- 200mg 10-20mg propoxyphene Tramadol ----50-100 ------- 50-100 duration 3-4hrs 3-4 hrs 4-8 hours 2-3 hours 1.5 --- ---------- 3-4 hours 3-4 hours 3-4 hours 3-7 hours Conversion to Oral • • • • • • Calculate total daily requirement with PCA Convert to IV morphine Convert to Oral morphine Convert to alternate opioid 75 % as ATC 25% as rescue Factor in incomplete cross tolerance especially with oxycodone and Methadone Prior to Oral Conversion • Patient able to tolerate oral fluids • Oral therapy started prior to removal of PCA • Pain control predictable and stabilized • IV to oral conversion calculated • Side effects under control • multimodal therapy started to be used PCA to Oral Oxycodone Conversion Table MSO4 HydroFentanyl morphone OxyContin Q 12 h Oxycodone IR (q 3h prn) 24-hour opioid < 20 mg < 4 mg < 300 mg 0 5-10 mg 30 mg 6 mg 500 mg 10 mg 5-10 mg 40 mg 8 mg 650 mg 20 mg 5-10 mg 50 mg 10 mg 800 mg 30 mg 10 –15 mg 60 mg 12 mg 1000 mg 30 mg 10 –15 mg 70 mg 14 mg 1200 mg 40 mg 10 –15 mg 80 mg 16 mg 1400 mg 40 mg 10 –15 mg Ginsberg B, Anesthes & Analgesia 1998 Oral Opioid Comparison Oxycodone Hydromorphone Hydrocodone • Long track record • Avoids “M” word • No toxic metabolites • ? immune function • Formulations –Immediate release –Controlled release • Long track record • Avoids “M” word • No toxic metabolites • ? immune function • Formulations –Immediate release –Sustained release (Fall 2001) • Long track record • Avoids “M” word • No toxic metabolites • ? immune function • Formulations – Immediate release – Combinations Acetaminophen o Ibuprofen Example of Conversion • Total morphine for 24 hours on PCA= 60mg Want to convert to Oxycodone. 60 mgm of MS IV( x 3) = 180 mgm oral. To convert to oxycodone x by 1.5 = 120 mg oxycodone 75% as ATC = 90 mg = 40 mg Q 12 , but factor in 50% less for ICT = 20 mg q 12 hourly 25% as rescue = 30 mg or 5 mg Q 4-6 hourly PRN Long Acting Opioids for ATC • • • • MS Contin 15,30,60 mgm Oxycontin 10,20,40,60,80 mgm Methadone 5, 10, 20 mgm Fentanyl patch 25, 50,75,100 mcg Methadone (Dolophene) • • • • • • • • • • Long acting Lower addiction potential Cheap Lower tolerance profile For the opioid addict No active or toxic metabolites No renal excretion No dependence on hepatic function Long elimination half life 8-12 hour analgesic action Methadone • • • • • • • Start of at lowest dosage 5 mgm Q 12 hourly Warn patient about dangers of PRN Increase only after 72 hours if needed If indicated increase to 5 mg Q 8 hourly Increase to 10 or 7.5 mg slowly Strongly advise against iv administration Oxycodone • High bioavailability compared to MSO4 • No toxic metabolites • Less tolerance compared to MSO4 • Higher incidence of euphoria • Expensive • No “M” word The Fentanyl Patch • Indications for use – – – – – Around the clock delivery of opioids Allergy to long acting oral opioids Severe nausea and vomiting Unable to swallow Severe constipation • Beware – – – – Opioid naïve Febrile patient Elderly Drug abuser Conversion Chart for Starting Dose of Transdermal Fentanyl Fixed-combination short-acting opioids (6/day): – Lorcet 5 mg/500 mg – Lortab 5 mg/500 mg – Percocet 5 mg/325 mg – Percodan 5 mg/325 mg – Tylenol + Codeine 30 mg/325 mg – Tylox 5 mg/500 mg – Vicodin 5 mg/500 mg One 25 mcg/h transdermal fentanyl patch/3 days (72 hours) Long-acting opioids(2/day): – OxyContin 20 mg – MS Contin 30 mg (Adapted from Duragesic PI, 2001) Multiple patches may be used for doses exceeding 100 mcg/h. Doses up to 6oo mcg/h have been evaluated in clinical trials. Renal Failure • • • • • • • Methadone Dilaudid Oxycodone Hydrocodone Morphine Fentanyl Demerol NEUROTOXICITY SEDATION TOLERANCE Liver Failure • • • • • • • Methadone Dilaudid Oxycodone Hydrocodone Morphine Fentanyl Demerol All pretty much OK, but halve dose Side Effects of Opioids • • • • • • Nausea Sedation Constipation Pruritus Myoclonus Sweating Dependence • Physical dependence • Psychological dependence • Pseudo addiction Recognizing the Addict • • • • • • • • Refuses drug screen Focus on narcotics Wants demerol or fentanyl Wants Xanax and soma Hourly or daily escalations Conflicts with care givers Family issues Obvious stigmata Strength 10 mgm 2o mgm 40mgm 80mgm 160 mgm Licit Retail $1.25 $2.30 $4.0 $6.0 $14 Illicit Retail $5-10 $10-20 $25-40 $65-80 $100-200 Cincinatti Police Department 50c to $1.5 per milligram oxycodone Non Opioid Adjuvants • • • • • Antidepressants Anticonvulsants Anti-inflammatories Acetominophen Tramadol Acetaminophen Guidelines • Short-term NHCOCH3 – < 4 gm / day • Long-term – < 3.2 gm /day – < 2.4 gm /day, elderly, debilitated OH Acetominophen Content Tylenol Tylenol liquid Tylenol drops Tylox Vicodin Lortab Norco zydone Wygesic 160 325 500 80 160 500 80 100 500 500 750 500 650 325 400 650 650 Tricyclic Antidepressants: Adverse Effects • Commonly reported AEs Fewest (generally AEs anticholinergic): • Desipramine – blurred vision – cognitive changes – constipation – dry mouth – orthostatic hypotension – sedation – sexual dysfunction – tachycardia – urinary retention • Nortriptyline • Imipramine • Doxepin Most AEs • Amitriptyline Caveats With the Antidepressants •Start at lowest dose available •Escalate slowly…every 10 -14 days •Slow weaning, over a week •Beware of drug interactions •Check for •Glaucoma •Prostatic obstruction •Heart block Drug Interactions With Antidepressants • • • • • • • • Coumadin Alcohol ( cold medications) Appetite suppressants Quinolone antibiotics Antihistamines Tramadol Anti epileptics Bronchodilators The Anti Epileptic Drugs • Carbamazapine (Tegretol) • Gabapentin (Neurontin) • Oxcarbezapine (Trileptal) • • • • • Topiramate ( Topramax) Zonisamide ( Zonergan) Levetiracetam( Keppra) Lamotragine ( Lamictal) Valproate ( Depakote) Gabapentin in Neuropathic Pain Disorders • • • • FDA approved for postherpetic neuralgia Anticonvulsant: uncertain mechanism Limited intestinal absorption Usually well tolerated; serious adverse effects rare – dizziness and sedation can occur • No significant drug interactions • Peak time: 2 to 3 h; elimination half-life: 5 to 7 h • Usual dosage range for neuropathic pain up to 3,600 mg/d (tid–qid)* *Not approved by FDA for this use. Suggestions with Gabapentin • • • • • • • • Start as low as possible…..100 mgm q HS Increase slowly by 100 mgm every three days Caution regarding driving Increase to 1200 mgm and assess pain relief If > 50% relief, wait two weeks and reassess Increase to maximum of 3600 mgm Do not exceed 1200 mgm in elderly Elixir in children mgm/kilo The Arachidonic Acid Cascade and COX-1 and COX-2 Inhibition Arachidonic acid COX-1 X Body Homeostasis • Gastric integrity • Renal function • Platelet function COX-2 Traditional NSAID X X Selective COX-2 Inhibitor Inflammation Pain Needleman P, et al. J Rheumatol. 1997;24: 6-8. Simon LS, et al. J Clin Rheumatol. 1996;2:135-40. COX-2–Specific Inhibitors Generic Name Celecoxib Brand Name Celebrex® Approval Year 1998 Rofecoxib Vioxx® 1999 Valdecoxib Paracoxib Etoricoxib Bextra® 2001 The COX 2 Inhibitors • • • • • Rofecoxib 25-50 mg daily (Vioxx) Celecoxib 100-200mg daily (Celebrex) Valdecoxib 10-20 mg daily (Bextra) Etrocoxib Paracoxib (iv use) • • • • • • • • • • Contra Indications to COX2 Therapy Previous side effects with COX2 inhibitors Allergy to sulpha drugs History of previous GI bleed pregnancy History of perforated gastric ulcer Esophageal varices Bronchospastic disease Renal dysfunction Coronary artery disease needing aspirin Congestive heart failure The Muscle Relaxants • Most act by central mechanisms • Most produce sedation • Most have anticholinergic side effects • Some are highly addictive • Most produce little local relaxation The Muscle Relaxants • Centrally acting relaxants – – – – Metaxalone(Skelaxin) Cyclobenzaprine (Flexeril) Methocarbamol (Robaxin) Carisprodol (Soma) • GABA agonists – Alprazolam (Xanax) – Diazepam (Valium) – Lioresal (Baclofen) • Alpha 2 agonists – Tizanidine ( Zanaflex) Beware of sedation, addiction and anticholinergic side effects The Muscle Relaxants • Centrally acting relaxants – – – – Metaxalone(Skelaxin) Cyclobenzaprine (Flexeril) 10mg and max at 40mg Methocarbamol (Robaxin) Carisprodol (Soma) highly addictive • GABA agonists – Alprazolam (Xanax) highly addictive – Diazepam (Valium) high abuse potential – Lioresal (Baclofen) 10 mg daily and max at 40mg. • Alpha 2 agonists – Tizanidine ( Zanaflex) 2mg q hs and escalate to 8mg Case Example •45 y.o. female with sickle cell disease •Admitted with severe back and left hip pain •Frequent visits to the ER for pain. Gets demerol •Takes Soma, Xanax and Vicodin for pain •History of cocaine, tobacco and THC abuse •Hb 5gms, severe muscle spasm lower back, decreased ROM left hip. •Placed on demerol 25-50 mg iv q 2 hourly PRN, Vicodin 10/500 tabs 1-2 q 4-6 hrly. •Continual demands for more demerol and yelling at nurses Take Home Message • Identify the pain generator • Identify and treat underlying disease(diabetes, HIV, Depression) • Assess before you treat • Start low and go slow • Use rational poly-pharmacy, but not shotgun Rx. • Factor in age, hepato-renal function • Monitor for abuse and document • Identify and treat side effects early • Be cost effective • Communicate with patient and family • Obtain pain service consult when you feel necessary Hermann Acute Pain Service 713-606-7100 Pager 713-704-3010 0ffice Good Luck and Thank You for Your Attention Questions?