A Comprehensive Review of Medications to Treat Pain

A Comprehensive Review of Medications to Treat Pain
Kelly W. Jones, Pharm.D., BCPS McLeod Family Medicine Center Grand Strand Advanced Practice Nurses Association 4/28/2017

Disclaimer I have no conflict of interest relating
in the material covered today. I do not serve on any speaker bureau. I do not have any personal grants concerning the area of discussion today.

Objectives Discuss the opioids in schedule CIII to CV and any clinical pearls associated with each drug Describe efficacy based on potency. List evidence-based efficacy outcomes for all medications discussed Discuss the recent FDA alert on acetaminophen and discuss the concept of synergy Describe the role of analgesic adjunctive agents for patients with chronic pain. Dosage and efficacy will be discussed Review side effects of each drug and describe ways the practitioner can aid in reducing these side effects Review the pharmacotherapy of NSAIDs

Let’s Review the CS Schedules
“Controlled Substance" - any drug or substance which is subject to or has the potential for abuse or dependence (physical or psychological)

Controlled Substance Act
Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970 Signed by President Nixon on October 27, 1970 He believed the drug problem in America was out of hand in the 60’s Now you had to register with the DEA (Drug Enforcement Administration of the Department of Justice Changes in schedule are requested by DEA, and FDA or by any organization who petitions the DEA DEA prosecutes violators of these laws This CSA was preceded by the Harrison Narcotic Act US Pharmacists, 2013

Harrison Narcotic Act of 1914
CSA replaced the Harrison Act The purpose of the act was to enforce treaty obligations to regulate international commerce in opiates. Manufacturers, pharmacists, physicians, distributers had to pay a fee and required to keep records of prescribing and dispensing It was not an Act to control behavior Many physicians were put in jail resulting from the misinterpretation of the Harrison Act Law enforcement arrested physicians who prescribed narcotics to addicts but it really was a record keeping law

Scheduling a Medication by the Attorney General

Recent Reclassifications
DONE a fake marijuana some state (Texas, ND) have restricted but not federal

Schedule for Controlled Substances Generic Name
Schedule II Fentanyl, hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, hydrocodone Cocaine Amobarbital, secobarbital, pentobarbital, barbiturate combinations Amphetamine complex, dexmethylphenidate, dextroamphetamine, methylphenidate, Schedule III Codeine combinations, buprenorphine Ketamine Butalbital Anabolic steroids (not abuse potential but for cheating) Schedule IV Alprazolam, chlordiazepoxide, clonazepam, diazepam, lorazepam, oxazempam, temazepam, triazolam; chloral hydrate; zolpidem, zaleplon Carisoprodol Phenobarbital tramadol Schedule V Codeine preparations (1mg/ml) Pregabalin Diphenoxylate/atropine Lacosamide (Vimpat®)

Schedule 1 CI Schedule 1 Drugs High abuse potential
No current accepted medical use Usually no safety data Drugs 174 listed drugs Many are 2,5-dimethoxy-4-ethylamphetamine 3-methylfentanyl (White China) Peyote (cactus mescaline) Psilocyn (mushrooms) THC at the moment Heroin (diacetylmorphine) LSD MDNA Cathinones Methylamphetamine

Schedule 2 CII The medication has a high potential for abuse
High reward Fast onset Abuse leads to dependence Safety and efficacy are known Medications 67 listed medications Cocaine Most Opioids Codeine (as single agent), morphine, etc Amphetamines Barbiturates

Schedule 3 Less abuse potential than CI or CII Slower onset
Less Reward Safety and efficacy are known Medications 104 listed medications Opioids: codeine combinations, buprenorphine Butalbital Secobarbital in suppository form Anabolic steroids

Schedule 4 CIV Even lower abuse potential than CI to CIII Slower onset
Less Reward Safety and efficacy are known Medications 75 listed medications Benzodiazepines and other sleepers Sedative hypnotics Phenobarbital Carisoprodol Diet pills (phentermine, diethylpropion) Tramadol Ones of interest – flunitraepam (Rohypnol); Lorcaserin (Belviq), Modafinil (Provigil)

Schedule 5 CV Lowest abuse potential
Many of these meds were noted to cause euphoria in clinical trials There is limited dependence Medications 10 listed medications Codeine syrup preps (Robitussin AC®) Diphenoxylate (Lomotil®) Ezogabine (Potiga®) Lacosamide (Vimpat®) Pregabalin (Lyrica®)

New Rule December 19, 2007 Multiple CII prescriptions Up to 90 day supply Same drug on 3 different prescriptions Must contain actual date written with instructions for next fill date (“do not fill before” date) Pharmacists DO NOT have the ability to change “do not fill before” date even with verbal authorization from the physician

Partial Filling Terminally ill or long-term care facility (LTCF) patients Same prescription for up to 60 days “Terminally ill” or LTCF must be written on Rx For all others: must fill within 72 hours of the partial fill

Phoning For a CII emergency Only amount needed
Written, signed Rx must be received within 7 days by the pharmacist Can mail Rx but must be postmarked within 7 days On the Rx must say “Authorization for Emergency Dispensing” with original date of verbal order If Rx not received within timeframe must be reported to the DEA

Other SC law issues CIII-CIV CII May be faxed or called in
Must not exceed a 90 day supply Rx must be dispensed within 6 months of issue Up to 5 refills or 6 months May be refilled no sooner than 48 hours CII Must not exceed a 31 day supply Rx must be dispensed within 90 days of issue No refill or use the 3 Rx rule

CSA Registrant Population as of 01/03/2008
SCPhA 2008 Tech Connection CSA Registrant Population as of 01/03/2008 Total Population: 1,280,489 Practitioner Mid-Level Practitioner Pharmacy Hospital/Clinic Manufacturer Distributor Researcher Dog Handlers Analytical Labs Importer Exporter Narcotic Treatment Program 1,040,241 143,499 65,497 16,389 510 827 5,963 2,164 1,551 186 235 1,243 Caverly, Mark. "Drug Diversion: the Inside Scoop." American Pharmacists Association. APhA2008 Annual Meeting. San Diego Convention Center, San Diego. 17 Mar

DHEC Registrants Pharmacies 1,077 Physicians 10,774 Dentists 2,032
SCPhA 2008 Tech Connection DHEC Registrants Pharmacies 1,077 Physicians 10,774 Dentists 2,032 Veterinarians 868 Optometrists 360 NPs PAs Hospitals/Clinics Others Total ,163 Harling, Wilbur. “Controlled Substances Regulatory Update." SC College of Pharmacy – USC Campus PHRM Apr

SCPhA 2008 Tech Connection DEA Numbers DEA registration number has 7 digits, usually preceded by two alphabetic characters Prior to Oct. 1, 1985 DEA numbers started with an ‘A’; after that new registrations started with a ‘B’, and now some begin with an ‘F’. Midlevel practitioners registration numbers begin with an ‘M’ Second letter is the first letter of practitioner’s last name Examples: AB BS MJ

BB1234563 Checking DEA Number Add 1st, 3rd, 5th Digits together
SCPhA 2008 Tech Connection Checking DEA Number BB Add 1st, 3rd, 5th Digits together = 9 Add 2nd, 4th, 6th Digits & Multiply by 2 ( ) 2 = 24 Add both sums together = 33 Last digit of sum same as DEA last digit Registrations issued initially prior to October 1, 1985 received A After that date, number starts with B Registration numbers starting with M are assigned to Mid-Level practitioners Someone other than a physician, dentist, vet, or podiatrist who is licensed, registered, or otherwise permitted by US ot dispense a controlled substance in the course of professional practice It is up to the pharmacist to make sure the Rx prescribed are within the state’s parameters for prescribing

SCPhA 2008 Tech Connection Which of the following digits would make this DEA number an authentic one: BC445987__ 6 7 8 9 = 17 = 20 X 2 = 40 = 57 Answer: B = 7 Answer: B = 17 = 20 X 2 = 40 = 57 7

Chronic Pain is Complex
Patient “A”Pain 8/10 Patient “B” Pain 8/10 Genetics Depression & Anxiety Social Disability Physical Injury Environmental Stressors Functional Substance Use Cultural Background Cultural Background Environmental Stressors Functional Disability Genetics Physical Injury This is just a cartoon to show you two patients, patient A and patient B. They both have identical pain scores – that is, eight out of 10 – when you ask them to rate their pain. So when you look at what’s beneath that pain score, what’s causing them to feel that type of pain, on patient A, there’s a large piece of physical injury, functional disability with some environmental stressors. But when you look on patient B, there’s much more social disability, depression, anxiety, and there’s substance abuse. And so you need to look deeper beyond just the patient’s pain score as to what might be causing them to feel this way because all of these issues need to be addressed when we’re talking to our patients. Cognitive Dysfunction Social Disability Depression & Anxiety With permission, SCOPE of Pain, 2015 Gatchel RJ. Am Psychol Nov;59(8):

Psychiatric Co-Morbidities
Condition Prevalence Chronic Pain Patients References Depression % Cheatle M, Gallagher R, 2006 Dersh J, et al., 2002 Anxiety Disorders % Knaster P, et al., 2012 Personality Disorders % Polatin PB, et al. 1992 Fischer-Kern M, et al., 2011 PTSD 49% veterans 2% civilians Otis, J, et al., 2010 Substance Use Disorders % But we also know that it’s complicated by psychiatric co-morbidities. They are high prevalences of depression, anxiety, somatization, personality disorders, PTSD, and substance use disorders. And so we know that these conditions make pain worse, and pain makes them worse as well. With permission, SCOPE of Pain, 2015

Multidimensional Care
It’s More Than Medications Improve Quality of Life Restore Function Physical Exercise Manual therapies Orthotics TENS Other modalities (heat, cold, stretch) Psycho-behavioral CBT/ACT Tx mood/trauma issues Address substances Meditation SELF CARE Cultivate Well-being Reduce Pain The gold standard of care of chronic pain is a multidimensional approach that empowers the patient in self-care with goals aimed, as we talked about before, reducing pain, restoring function, and improving the individual’s quality of life. And we have many different approaches to choose from including psycho-behavioral approaches, physical approaches, procedures, and medications. For many patients with chronic pain, combining physical therapy, cognitive behavioral therapy, and activities such as daily exercise and meditation may be sufficient to reduce their pain, and when it’s not we use medications, procedures, and sometimes opioids. And we find that the responses to opioids and other medications may be better when the patient is engaged in a more comprehensive program. Medication NSAIDS Anticonvulsants Antidepressants Topical agents Opioids Others Procedural Nerve blocks Steroid injections Trigger point injections Stimulators Pumps TENS Transcutaneous Electrical Nerve Stim CBT Cognitive Behavioral Therapy ACT Acceptance and Commitment Therapy With permission, SCOPE of Pain, 2015

Things we can do! Rule out other mental illness.
Be aware of dosing. The higher the dose, the higher rate of death, hospitalization, unconsciousness and respiratory failure. Three times higher risk to die if OME dose is >200 mg/d From a compassionate standpoint I want to relieve pain, from a realistic standpoint, I want to improve function. BUT THERE IS VERY LITTLE EVIDENCE THAT THEY PROMOTE ENHANCED FUNCTIONAL LIFESTYLE, RETURN TO WORK OR OTHER FUNCTIONAL MEASURES. Motive matters with adolescents. The ones that divert a prescription or use the medication to sensation treat, they have problem behaviors. Adolescent children must be told that they will be approached to divert by friends and classmates. Adolescents mainly get their stash from parents. SC Rx Drug Abuse Summit, Columbia, SC, 11/16/2011

Is There Evidence? Systematic Review
Evaluate the evidence on the effectiveness and harms of opioid therapy for chronic pain They evaluated 39 studies out of 4209 potentially relevant articles “No study of opioid therapy versus placebo, no opioid therapy, or nonopioid therapy evaluated long-term (>1 year) outcomes related to pain, function or quality of life.” “No RCT evaluated opioid abuse, addiction, or related outcomes with long-term opioid therapy versus placebo or no opioid therapy.” Ann Intern Med 2015;162(4):276-86

Is There Evidence? One study has documented use of long term opioid therapy (>90 days of opioid within 12 months of a newly chronic pain diagnosis) versus no opioid therapy – the drug was associated with increase risk for the diagnosis of opioid abuse or dependence No study has evaluated the risk for falls, infections, or psychological, cognitive or GI harms in those on long-tern opioid therapy No REMS effectiveness data yet Ann Intern Med 2015;162(4):276-86

Their conclusion “Evidence is insufficient to determine the effectiveness of long-term opioid therapy for improving chronic pain and function. Evidence supports a dose-dependent risk for serious harms.” Serious harms (findings in single trials) One retrospective trial found increase risk of overdose event in patients prescribed opioids – 256/100,000 vs a rate of 36/100,00 in those NOT prescribed an opioid. Higher doses increase risk. Fracture risk – OR 1.27 180 days of opioids over 3 yrs = OR 1.28 for MI Opioid use is associated with increase use of ED meds and testosterone Motor vehicle accidents – OR 1.21 to 1.42 – 20 mg of OME Ann Intern Med 2015;162(4):276-86

Jones Black List Butalbital preps Carisoprodol or Soma® long term
Fiorinal®, Fioricet®, Sedapap®, Phrenilin® 12 different generic-brand names for Fioricet® i.e. Anolor, Esgic, Repan, Nonbac, Pacaps, etc Fiorinal #3 or Fioricet #3 contain codeine Carisoprodol or Soma® long term Meprobamate products (Miltown®) Stadol NS® Talwin NX® (pentazocine) Chronic high dose aspirin for pain Alka-Seltzer®,Goody Powder

Butalbital FDA indications Adverse events
Anxiety about preoperative treatment Used as a sleeper the evening before surgery No benefit over placebo for anxiety the next morning or number of nighttime awakenings Tension-type headache mg q4h prn (do not exceed 300 mg/day) Reduce dose in renal patients – lots of metabolites Adverse events Dependence and addiction Dose and duration dependent Withdrawal can be serious – seizures, hallucination, anxiety

Butalbital – all generic
Product Grid - butalbital/acetaminophen or aspirin/caffeine/codeine Fiorinal® - 50/325 aspirin/40 mg Fiorinal with Codeine® - 50/300/40/30 mg Fioricet® - 50/325 (or 300 mg)/40 mg (capsule) Many other trade names: Esgic® (tab), Zebutal®, Dolgic®, Margesic®, Vanatol LQ (liquid - 50/325/40 mg per 15 ml Fioricet with Codeine® - 50/300/40/30 mg Butalbital/acetaminophen – 50 mg/325 mg Marten-Tab®, Promacet®, Orviban CF® Butalbital/acetaminophen – 50 mg/650 mg Bupap®, Phrenilin Forte®, Tencon®

Margin of Safety

Margin of Safety Anesth Prog 2007;54:

Carisoprodol CIV Skeletal muscle relaxant 250 mg, 350 mg tabs
2004 marketing study showed that carisoprodol, metaxalone, cyclobenzaprine represent ~50% of a Rx’s for musculoskeletal pain Converts to meprobamate in the liver Meprobamate is a barbiturate-like in pharmacology Sedative/hypnotic, addicting Miltown® and Equanil® - antianxiety agents of the 50’s Most common side effects: dizziness (8%), headache (5%), somnolence (20%) 250 mg, 350 mg tabs 1 tablets 3 to 4 times/day

Carisoprodol Added isopropyl group Meprobamate

Carisoprodol Abuse Much abuse reported
It has been used to enhance the effect of alcohol and benzo’s Prevent the jitters during cocaine consumption Calming effect after cocaine use Used as an alternative to opioids for pain Adds relaxation and euphoria to other abused drugs Study of 40 users 40% used larger dose than prescribed 30% used it for an effect 10% used it to augment another med SMJ 2012;105(11):619-23

Carisoprodol Abuse Those on higher doses have the worse withdrawal
Withdrawal peaks after 4 days off carisoprodol Anxiety, tremors, muscle twitching, insomnia, hallucination, agitation Can impair driving Norway has banned the medication Specialty approved patients can be approved for use European Union members have discussed it Alabama was the first state to control it (1998) 18 other states joined in 2011 DEA classification to CIV in all states in 2012 SMJ 2012;105(11):619-23

Pain Ladder Morphine Oxycodone or Oxymorphone Hydrocodone or combo
Tylenol #3 + NSAID Tylenol #3 or Tramadol or buprenorphine NSAID + Acetaminophen NSAIDs Acetaminophen or nonacetylated salicylates Nonpharmacologic Approaches

Pain Ladder Fentanyl Hydromorphone Ladder Extension

Nonpharmacologic Approach
Comprehensive therapy with many approaches Spiritual advise Rest Exercise Biofeedback or Psychotherapy Heat/cool packs Hot baths Complementary medicine

Acetaminophen/APAP/Paracetamol or just Tylenol®
Analgesic No more than 4 grams per day Or 2600 mg 4 times a day - FDA Extra strength = 500 mg 5 grains = 325 mg Caution in alcoholics and those with liver disease 2 grams/day limit Caution with warfarin Drug of choice for OA??????

Acetaminophen is in the NEWS
Prescription acetaminophen products are limited to 325 mg per dose 3-year phase in period has concluded Not affecting OTC acetaminophen at this time New 160 mg/5 ml concentration liquid for infants and children, will contain oral syringe Watch for confusion with 80 mg/0.8 ml Acetaminophen as a rare cause for serious skin reactions – Steven’s-Johnson Syndrome, TEN, exanthematous pustulosis 1-3 weeks after ingestion (has occurred after 3 days) One study reports that acetaminophen can be the culprit in 20% of SJS cases FDA Alerts Asia Pac Allergy 2014;4(1):68-72

New Acetaminophen Study
Meta-analysis on acetaminophen for the treatment of low back pain or osteoarthritis Search of 9 databases, Cochrane 13 trials of good quality Full dose 4 gm/day Results Low back pain – lack of efficacy on pain and disability for immediate relief (<2 weeks) or short-term (2 weeks to 3 mths) Hip or knee osteoarthritis Statistically significant BUT clinically insignificant effect for immediate or short-term therapy Minimal adverse events Higher LFT’s in acetaminophen group (>1.5 times normal) Worth a try – let the patient tell you if they are pleased! BMJ 2014;350:hI225

Non-acetylated Salicylates
Does not interfere with platelet aggregation Most useful in patients with renal dysfunction and those on warfarin Rarely associated with GI bleeding Less likely to affect renal function Safe in aspirin allergic patients Salicylate toxicity is possible Can cause tinnitus “Weak” to “no” antiinflammatory effects No RCTs demonstrating efficacy in chronic pain Onset of action slower than NSAIDs Analgesic response is individual

Non-acetylated Salicylates Products
Diflunisal (Dolobid®) 500 mg - dose is 2 tabs loading dose, then 1 tab twice daily Generic price - $1.00 per tablet Choline magnesium trisalicylate (Trilisate®) 1000 mg tabs or 500 mg/5 ml liquid Typical dose is 1500 mg BID or 3,000 mg qhs Salsalate (Disalcid®) 500 mg, 750 mg tabs 3 g per day in 2-3 doses Magnesium Salicylate Doan’s Pills, DeWitts, Momentum - OTC

Self-Assessment Question
What is the difference between non-acetylated salicylates (NAS) and NSAIDs? A. NSAIDs have a longer duration of effect, requiring less dosing. B. NAS have weak to no antiinflammatory activity. C. NSAIDs have weaker effects on platelets and therefore less bleeding. D. NAS have a negative effect on lipids – lowers HDL.

Self-Assessment Question
The first NSAIDs was and still is? A. Ibuprofen (Motrin®) B. Indomethacin (Indocin®) C. Acetylsalicylic acid (Aspirin®) D. Acetaminophen (Tylenol®)

NSAIDs Allergy to aspirin = allergy to NSAIDs
If one NSAID does not work, does not mean others will not work Choose a quick-onset, short acting NSAID for acute conditions Choose a slower-onset, longer acting NSAID for more chronic conditions Analgesic effects are single dose Anti-inflammatory effects occur between days 7 and 14 During times of disease inactivity, decrease the dose to the lowest possible to maintain control Combination therapy with 2 NSAIDs only increases toxicity and has not been shown to produce any additive efficacy

Traditional NSAIDs Ibuprofen (Motrin®, Advil®
Diclofenac sodium (Voltaren®) Naproxen (Naprosyn® and EC Naprosyn®) Naproxen sodium (Anaprox®) Flurbiprofen (Ansaid®) Etodolac (Lodine®) Nalbumetone (Relafen®) Oxaprozin (Daypro®) Indomethacin (Indocin®) Tivorbex® (indomethacin) – new product! low dose, 20mg, 40 mg capsules Dosed tid for mild to moderate pain – use least time needed

Traditional NSAIDs you are not likely to use
Ketoprofen (Oruvail®) Sulindac (Clinoril®) Fenoprofen (Nalfon®) Piroxicam (Feldene®) Meclofenamate (no more Meclomen®, only generic) Mefenamic Acid (Ponstel®) Tolmentin (Tolectin®)

Quick-Onset, Short-Acting NSAIDs
Bromfenac sodium (DuractR) Off market Ketorolac IM or oral (ToradolR) Diclofenac potassium (CataflamR) Diclofenac (Zorvolex®) – 18 mg, 35 mg caps Solumetrix fine particle technology A dry milling technology that makes particles 50 to 200 times smaller and prevents agglomeration. Indicated for mild to moderate acute pain Makes the diclofenac function as a diclofenac potassium – comparable time to peak plasma concentrations, therefore more power with a lower dose Given three times a day $85 for either dose for #30 (10 days)

More to consider! Presupposition
Drugs in solution get faster peaks in the serum and therefore faster analgesic activity. Gelcap products might have more efficacy in patients OTC ibuprofen all come in liquid gelcap formulations New Advil® Film-coated (ibuprofen sodium, 256 mg) Uses an ion core technology that increase the speed of dissolution Marketed in a white box (others are blue and red)

Longest-Acting NSAIDs
Diclofenac (Voltaren XR®) Oxaprozin (Daypro®) Nalbumetone (Relafen®) Etodolac (Lodine XL®) Ketoprofen (Oruvail®)

Only one COX-2 inhibitor
Cox-2 Inhibitors Only one COX-2 inhibitor Celecoxib Celebrex® (now generic) Off Market Rofecoxib Vioxx® Valdecoxib Bextra® Cox-2 weighted Meloxicam Mobic® ($4 generic)

Even more to consider! Ophthalmic NSAIDs
Ketorolac (Acular®, Acular LS®) 0.5% 1 drop QID Generic 5 ml ($20),10 ml ($30) LS, 5 ml of 0.4% ($200) - for post-corneal refractive eye pain Diclofenac (generic) 0.1% 2.5 ml ($12), 5 ml ($20) Flurbiprofen (Ocufen®, generic) 0.03% 2.5 ml ($12)

Where I-NSAIDs are used!
Allergic conjunctivitis Eye irritation Dry eyes Analgesia Post-op inflammation due to cataract surgery

New NSAIDs for the eye! Bromfenac (Xibrom®) 0.09%
Indicated in post-op inflammation due to cataract surgery I drop twice a day 2.5 ml ($100), 5 ml ($190) Nepafenac (Nevanac®) 0.1% 1 drop three times a day 3 ml suspension ($175)

And yes – even more to consider!
Voltaren® Topical (diclofenac gel for OA) 100 gm of 3% Diclofenac (Pennsaid®) NSAID topical solution for OA of the knee, 150 ml ($260) 40 drops/knee four times a day Do not apply to open wounds Do not shower, bath, swim for 30 min Most common side effects Dry skin, contact dermatitis, GERD pain Diclofenac Potassium for Oral Solution (Cambia®) Oral solution for acute migraine, get level within 5 min max in 15 min 50 mg dose, mix powder in 1-2 oz of water Buy in a co-joined dose pack of three or a box of nine ($300) Diclofenac (Zipsor®) Liquid-filled capsule formulation for mild to moderate pain 25 mg, $260/#60

Unique NSAID Formulations
Diclofenac Sodium (Solaraze®) Actinic keratoses, twice daily for days – the drug continues to work 30 days after stopping the medication $1200, 10 gm Diclofenac epolamine 1.3% (Flector® Patch) NSAID patch for acute pain from strains, sprains, contusions Dose is one patch twice a day Do not apply to damaged skin Do NOT wear while bathing or showering Wash hands after application Come in a box of 2 envelopes, each envelope has 5 patches, $82

Unique NSAID Formulations
Ketorolac (Sprix®) Nasal spray NSAID for moderate pain 15.75 mg per nostril Dose is one spray per nostril every 6 to 8 hours prn, max 63 mg Only last 24 hours after open bottle NO indication in pediatrics Box of 5 bottles, $180 Naproxen + esomeprazole (Vimovo®) 375 mg/20 mg; 500 mg/20 mg Delay-release tablets Twice daily dosing $130, #60

Other Topical Ideas with NSAID’s
Get these through compounding pharmacies Sports injury formula Diclofenac 3%, Baclofen 2% Diclofenac 3%, Baclofen 2%, cyclobenzaprine 2%, gabapentin 6%, bupivacaine 2% Neuropathic pain formula’s Ibuprofen, baclofen 2%, amitryptyline 4%, lidocaine Other formula’s have flurbiprofen 10% or ketoprofen 10% or ketorolac 0.5% as NSAIDs Moss Goose Grease – Gabapentin 5%, ketoprofen 10%, lidocaine 5% +/ – ketamine 2%

The STEPS Approach Safety Tolerability Efficacy Price Simplicity

Going backward in our STEPS
Price and Simplicity Lots of selection on dosing Some are once a day – but some are cheaper and given more often Acute pain indications do not suffer with dosing frequency Lots of generics Efficacy Many reproducible studies Comparative trials versus ibuprofen, diclofenac, or naproxen No difference in efficacy Approved for OA, RA, dysmenorrhea, etc

Adverse Effects of NSAIDs
Central Nervous System effects tolerability Somnolence, dizziness – 2-5% Allergic Reactions safety and tolerability Angioedema to fixed-drug eruptions Gastrointestinal effects can be safety and tolerability Dyspepsia to gi bleeds Nephrotoxicity Safety Acute renal failure is rare, <1%, raise SCr Hepatotoxicity Hepatic necrosis and hepatitis are VERY rare

Managing NSAID Risks GI Bleed Risk, incidence 3-5/1000
Loads of papers – meta-analysis – cohort case control studies Bottom line statements There is a four fold increase in gi bleed in patients who use NSAID’s compared to those who don’t! Ibuprofen RR (0.3%) Diclofenac RR (0.6%) Indomethacin RR (1.2%) Estimated risk of hospitalization from a gi bleed is 0.17% per year. There is consensus that long-acting agents and higher doses are more risky PL Detail Document #290711

NSAID-Induced Ulcers Risk Reduction through Choice of Agent
High: aspirin, indomethacin, ketorolac, meclofenamate, piroxicam, tolmetin Medium: diclofenac, fenoprofen, flurbiprofen, ketoprofen, ibuprofen, naproxen, oxaprozin, sulindac, mefanamic acid Low: meloxicam, etodolac, nabumetone Lowest: celecoxib

Prevention of NSAID-induced ulcers
Misoprostol 200 mcg TID optimal dose (Ann Intern Med 1995;123:241-9) Any GI complication - ARR = 0.6%, NNT 167 Serious upper GI - ARR = 0.38%, NNT 263 40% will experience diarrhea, NNH 17 H2-blockers PPI’s ASTRONAUT Trial (N Engl J Med 1998;338(11):719-25) Omeprazole 20 mg healed NSAID ulcers better than ranitidine 150 mg twice a day (80% vs 63%, NNT 6) Increasing the dose to Omeprazole 40 mg added no benefit.

Chan Studies Study 1 Study 2
Purpose: Does celecoxib or diclofenac + omeprazole reduce the risk of recurrent ulcer bleeding in patients at high risk? 6 months; n = 290 Result: If you can’t afford celecoxib, then add a PPI to the NSAID of choice Study 2 Purpose: Will celecoxib and esomeprazole be better than celecoxib alone for the prevention of recurrent ulcer bleeding in patients with previous NSAID-induced ulcer bleeding who need continued NSAID therapy? Study 1: N Engl J Med 2002;347:

Chan Study #2 Results Esomeprazole dose used in the trial was 20 mg twice daily Lancet 2007;369: (May 12)

Renal Effects of NSAIDs
Incidence < 1/1,000,000 Renal prostaglandins maintain renal blood flow and glomerular filtration - NSAIDs can inhibit your ability to compensate Those at most risk older age, diabetes, renal insufficiency, heart failure

NSAIDs and CKD Systematic Review
Purpose: Should patients with CKD entirely avoid NSAIDs? Review observations Most of the trials were from observational data and not RCT’s – therefore the data is limited Large patient numbers (800 to 1.5 million) Low or moderate dose NSAIDs appear to be safe for patients with GFR of 30 to 90 mL/min High doses NSAIDs should be avoided, even though the risk of CKD progression was modest (RR 1.26) EE+ conclusion Careful use of NSAIDs may be worth the small risk in CKD progression in patients with severe OA. Monitor renal function frequently. Fam Prac 2013:30(3):247-55

Cardiovascular Risk Issues
FDA Alert 7/2015 Based on our comprehensive review of new safety information, we are requiring updates to the drug labels of all prescription NSAIDs The risk of heart attack or stroke can occur as early as the first weeks of using an NSAID The risk may increase with longer use of the NSAID The risk appears greater at higher doses Information is not sufficient for us to determine that the risk of any particular NSAID is definitely higher or lower than that of any other particular NSAID NSAIDs can increase the risk of heart attack or stroke in patients with or without heart disease or risk factors for heart disease Patients treated with NSAIDs following a first heart attack were more likely to die in the first year after the heart attack compared to patients who were not treated with NSAIDs after their first heart attack There is an increased risk of heart failure with NSAID use

Cardiovascular Risk Issues
There seems to be a true signal for the increase risk of CV events (MI, stroke, death) in all patients taking NSAIDs. Incidence 1-4/1000 NSAIDs upset the balance between thromboxane A2 (vasoconstricting PG) and the opposing prostacyclin (vasodilating PG) leading to vasoconstriction, platelet aggregation and thrombosis. COX-2’s have more risk because: COX-1 produces thromboxane A2 COX-2 produces prostacyclin It is thought that naproxen is the safest on CV disease outcomes and the theory is that it has sustained COX-1 inhibition Diclofenac may have the highest risk as it had sustained COX- 2 inhibition. PL Detail Document #290711

NSAID use following an MI
Purpose: Does the increase risk of death following acute MI associated with NSAIDs use decline over time? Retrospective cohort Danish trial Took patients having an MI between 1997 and 2009 N = 99,187; mean age 69; 36% female Using NSAIDs increase death during the 5 year period after index MI (HR ) 19 more CV events for every 1000 patients treated Diclofenac had a somewhat higher risk Naproxen had a somewhat lower risk Circulation 2012;126(16):

Vascular Risk Meta-Analysis
280 placebo trials, n = 120,000 470 NSAID comparator trials, n = 230,000 Most trials lasted < 1 year We await the PRECISION Trial Outcome NSAID Placebo NNH Nonfatal MI, nonfatal stroke, death from vascular dz COX-2, 1.2% 0.8% 250 Death all-cause COX-2, 1.7% 1.4% 333 Admissions from HF COX-2, 0.7% 0.3% Lancet, online publication, May 30, 2013

NSAIDs and Hypertension
Mechanism – sodium retention and vasoconstriction Risk – obese men, elderly, those with diabetes, HF, CKD OK to use if BP is in control – best time to start the NSAID CCB are less likely to cause a problem ACEI, ARB, Thiazide may be affected by the NSAID Happens with all NSAIDs Might be best left to occasional use. 2011 PL Detail Document #271211

The Newest Risk – Atrial Fibrillation
Prospective population-based cohort Outcome – atrial fib with use of NSAIDs Mean age 69, 58% female, follow-up 13 yrs A. fib risk as compared to non-users, HR 1.76 Within 30 days of stopping the NSAID, HR 1.84 NSAID use is associated with an increase risk of a fib BMJ Open 2014;4:e004059

Other News on NSAIDs NSAIDs aid CCB in delaying onset of labor in women at risk of preterm labor. NSAIDs delayed labor by 48 hours. BMJ 2012;345:e6226 Naproxen has always been special in migraine treatment – added to sumatriptan improves efficacy Cochrane Database 2013, CD008541 NSAIDs relieve discomfort caused by the common cold – there was no improvement in respiratory symptoms like cough, runny nose Cochrane Database 2013, CD006362

Pain Ladder Morphine Oxycodone or Oxymorphone Hydrocodone or combo
Tylenol #3 + NSAID Tylenol #3 or Tramadol or buprenorphine NSAID + Acetaminophen NSAIDs Acetaminophen or nonacetylated salicylates Nonpharmacologic Approaches

Tylenol #3 Codeine 30 mg + acetaminophen
Chronic codeine causes lots of side effects: Constipation Urinary retention Tylenol #2 contains 15 mg of codeine Tylenol #4 contains 60 mg of codeine Empirin with Codeine® (codeine and aspirin) 325mg/30mg; 325mg/60mg

Tramadol CIV Binary analgesic Drug interactions
Weak opioid + SNRI Drug interactions Seizure risk Those on SSRI’s/SNRI’s/TCA High doses Those with seizure risk Can increase INR in warfarin patients, check INR in 3 days Cross-sensitive allergy with codeine is possible There are similar metabolites Regular release and extended release products (100 mg, 200 mg, 300 mg) Combination with acetaminophen (Ultracet®)

Tramadol CIV Most common side effects Dosing Formulations
Flushing (16%), pruritus (12%) Constipation (10-46%), Dizziness (7-33%), headache (3-32%), insomnia (1-12%), somnolence Dosing Best to start 50 mg of regular release or 100 mg ER Work up in dose Titrate regular release every 2 days if needed, max 300 mg/day Titrate extended release every 5 days Formulations Reg release, ER tablet, oral suspension 10 mg/ml, ER capsule (ConZip®)

Buprenorphine – The new Darvocet®?
Indication Moderate to severe chronic pain Continuous formulation patch CIII schedule Takes up to 3 days to see efficacy See quantifiable levels in 17 hours Half-life is 26 hours

Buprenorphine (Butrans®)
Efficacy N=5,415 patient experience Can be used in opiate naïve patients Four 12 week trials Two of the 4 trials showed no efficacy over placebo Low back pain trial improvement was modest NNT 10 for 50% reduction in pain scores vs placebo ~10% stopped therapy due to the lack of effect in trials Comparative trials 5 mcg vs 20 mcg/hr 30% reduction in pain scores of higher dose

Buprenorphine (Butrans®)
Price Expensive ~$100.00/patch 5 mcg/hr; 10 mcg/hr; 20 mcg/hr Simplicity Weekly patch, apply to upper arm, chest, back or side Alternate site application Avoid external heat sources Do not cut Can tape edges if needed Available in box of #4 with 4 patch-disposable units

FYI - New Dosage Forms for Pain
Xartemis XR® extended release oxycodone/acetaminophen 7.5 mg/325 mg – 2 tabs every 12 h Oxycodone (Oxecta®) Immediate release that deter abuse Hard to crush or dissolve Oxycodone + naloxone (Targiniq ER®) 10/20/40 mg with naloxone Dose q 12h

New Dosage Forms for Pain
Buprenorphine/Naloxone (Zubsolv®) CIII Maintenance treatment of opioid dependence SL tablet – 1.4 mg; 5.4 mg More bioavailability that the generic SL versions Buprenorphine/Naloxone (Bunavail®) CIII Buccal film formulation 2.1 mg buprenorphine/0.3 mg naloxone; 4.2 mg/0.6 mg; 6.3 mg/1 mg Dose for maintenance 8.4 mg/1.4 mg

Very Unique Medication
Evzio® - naloxone auto-injector for opioid overdose Comes with electronic voice instructions and a trainer kit Device is used even when you are not sure of the exact problem Use device Call 911

New for Pain Hydrocodone extended-release Zohydro ER® CII
Indication: management of pain that requires daily, around-the- clock, long-term opioid treatment It is NOT a “prn” medication Zohydro ER® CII First non-acetaminophen hydrocodone product Capsules 10, 15, 20, 30, 40, 50 mg 10 mg, #60 cost $375 Dosed every 12 hours Do not crush, chew, dissolve Massachusetts tried to ban this product

New for Pain Hydrocodone extended-release Hysingla ER®
20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 100 mg and 120 mg film-coated tablets Single daily dose

Respecting the Adjuvant
Definition Adjuvant analgesic describes any drug with a primary indication other than pain, but with analgesic properties. They are usually prescribed with a primary analgesic (opioid) in cancer pain. Can be used first-line in nonmalignant pain

Adjuvant selection Diverse group of medications Few comparative trials
Very few trials in cancer patients Selection depends on a variety of assessment criteria Type of pain (bone, neuropathy) Comorbid conditions Anticonvulsant in a patient with seizures Antidepressant in a patient with depression

Dosing guidelines Avoid starting 2 adjuvant analgesics
Start low, go slow Consider side effects and drug interactions Taper and discontinue any adjuvants that do not provide pain relief

Multipurpose Adjuvant Analgesics
Tricyclic antidepressant drugs Corticosteroids Anticonvulsants Calcitonin Bisphosphonates Lidoderm® Capsaicin Qutenza® topical Rx patch for postherpetic neuralgia

Pregabalin (Lyrica®) CV due to euphoria reported in recreational users
Chemically designed to have greater diffusion across BB barrier Inhibits neuronal excitability centrally through binding to the alpha2 subunit on calcium channels – prevents release of neurotransmitters (glutamate, NE, serotonin, dopamine) Indications: neuropathy, fibromyalgia, partial seizure, postherpetic neuralgia, RLS Also used for anxiety, and sleep-modulating (decreasing nighttime awakening) Anesth Analg 2007;105:

Pregabalin (Lyrica®) Very water soluble (no metabolism)
Dose must be adjusted in renal patients No drug interactions No studied dose conversion of gabapentin to pregabalin Recommended to taper gabapentin over a week and add pregabalin Availability 25, 50, 75, 100, 150, 200, 225, 300 mg capsules Oral solution 20 mg/ml Very pricy - $350-$450

Pregabalin (Lyrica®) Side effects
Somnolence 30% Dizziness 22% Dry mouth 9% Peripheral edema 6% Blurred vision 6% Weight gain 5% Difficult concentration or attention 5% Can you use both? Not CI, but more side effects

Pregabalin (Lyrica®) Dosing Diabetic Peripheral Neuropathy
Start 50 mg tid and increase to 100 mg tid in a week Doses of 600 mg/day has been studied but more side effects and no greater efficacy One approach is to titrate to 100 mg tid, give 4 weeks for efficacy, if there is none try 200mg tid Fibromyalgia 75 mg bid, increase to 150 tid in week, max dose is 225 mg bid (450 mg/day) Postherpetic neuralgia Start 75 mg bid or 50 mg tid Increase to 75 mg bid TO 150 mg tid Increase to 600 mg/day after 4 weeks if needed RLS mg 1-3 hrs before bedtime

Pregabalin (Lyrica®) Efficacy Indication Number of trials NNT
Diabetic neuropathy 3 4 Postherpetic neuralgia 3-6 Fibromyalgia Superior to placebo at 8 wks Added to celecoxib is more effective than either alone Refractory neuropathy 1 5 for >30% reduction in pain Anesth Analg 2007;105:

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