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A Comprehensive Review of Medications to Treat Pain

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Title: A Comprehensive Review of Medications to Treat Pain


1
A Comprehensive Review of Medications to Treat
Pain
  • Kelly W. Jones, Pharm.D., BCPS
  • McLeod Family Medicine Center
  • kjones_at_mcleodhealth.org

Grand Strand Advanced Practice Nurses Association
2
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.

3
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

4
Lets 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)

5
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 60s
  • 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
6
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

7
Scheduling a Medication by the Attorney General
8
Recent Reclassifications
DONE
a fake marijuana
some state (Texas, ND) have restricted but not
federal
9
(No Transcript)
10
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)
11
Schedule 1 CI
  • Schedule 1
  • 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

12
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

13
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

14
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)

15
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)

16
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

17
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

18
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

19
Other SC law issues
  • CIII-CIV
  • 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

20
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. 2008.
21
DHEC Registrants
  • Pharmacies 1,077
  • Physicians 10,774
  • Dentists 2,032
  • Veterinarians 868
  • Optometrists 360
  • NPs 936
  • PAs 210
  • Hospitals/Clinics 491
  • Others 415
  • Total 17,163

Harling, Wilbur. Controlled Substances
Regulatory Update." SC College of Pharmacy USC
Campus PHRM 446. 17 Apr. 2008.
22
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
    practitioners last name
  • Examples AB 1234563
  • BS 4273102
  • MJ 3614511

23
Checking DEA Number
  • BB1234563
  • Add 1st, 3rd, 5th Digits together
  • 1 3 5 9
  • Add 2nd, 4th, 6th Digits Multiply by 2
  • (2 4 6) 2 24
  • Add both sums together
  • 9 24 33
  • Last digit of sum same as DEA last digit

24
  • Which of the following digits would make this DEA
    number an authentic one
  • BC445987__
  • 6
  • 7
  • 8
  • 9
  • 0
  • 4 5 8 17
  • 4 9 7 20 X 2 40
  • 17 40 57
  • Answer B 7

25
(No Transcript)
26
Chronic Pain is Complex
Patient APain 8/10
CulturalBackground
EnvironmentalStressors
Functional Disability
Genetics
Physical Injury
Cognitive Dysfunction
Social Disability
Depression Anxiety
With permission, SCOPE of Pain, 2015
Gatchel RJ. Am Psychol. 2004 Nov59(8)795-805.
27
Psychiatric Co-Morbidities
Condition Prevalence Chronic Pain Patients References
Depression 33 - 54 Cheatle M, Gallagher R, 2006
Depression 33 - 54 Dersh J, et al., 2002
Anxiety Disorders 16.5 - 50 Knaster P, et al., 2012
Anxiety Disorders 16.5 - 50 Cheatle M, Gallagher R, 2006
Personality Disorders 31 - 81 Polatin PB, et al. 1992
Personality Disorders 31 - 81 Fischer-Kern M, et al., 2011
PTSD 49 veterans 2 civilians Otis, J, et al., 2010
PTSD 49 veterans 2 civilians Knaster P, et al., 2012
Substance Use Disorders 15 - 28 Polatin PB, et al. 1992
Substance Use Disorders 15 - 28 Cheatle M, Gallagher R, 2006
With permission, SCOPE of Pain, 2015
28
Multidimensional Care
Its More Than Medications
TENS Transcutaneous Electrical Nerve Stim CBT
Cognitive Behavioral Therapy ACT Acceptance and
Commitment Therapy
With permission, SCOPE of Pain, 2015
29
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 gt200 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
30
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 (gt1 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 2015162(4)276-86
31
(No Transcript)
32
Is There Evidence?
  • One study has documented use of long term opioid
    therapy (gt90 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 2015162(4)276-86
33
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 2015162(4)276-86
34
Jones Black List
  • Butalbital preps
  • 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

35
Butalbital
  • FDA indications
  • 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
  • 50-100 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

36
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

37
Margin of Safety
38
Margin of Safety
Anesth Prog 200754118-129
39
Carisoprodol CIV
  • Skeletal muscle relaxant
  • 2004 marketing study showed that carisoprodol,
    metaxalone, cyclobenzaprine represent 50 of a
    Rxs 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
    50s
  • Most common side effects dizziness (8),
    headache (5), somnolence (20)
  • 250 mg, 350 mg tabs
  • 1 tablets 3 to 4 times/day

40
Carisoprodol
Added isopropyl group
Meprobamate
41
Carisoprodol Abuse
  • Much abuse reported
  • It has been used to enhance the effect of alcohol
    and benzos
  • 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 2012105(11)619-23
42
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 2012105(11)619-23
43
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
44
Pain Ladder
Fentanyl
Hydromorphone
Ladder Extension
45
Nonpharmacologic Approach
  • Comprehensive therapy with many approaches
  • Spiritual advise
  • Rest
  • Exercise
  • Biofeedback or Psychotherapy
  • Heat/cool packs
  • Hot baths
  • Complementary medicine

46
Acetaminophen/APAP/Paracetamolor 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??????

47
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 Stevens-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 20144(1)68-72
48
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 (lt2 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 LFTs in acetaminophen group (gt1.5 times
    normal)
  • Worth a try let the patient tell you if they
    are pleased!

BMJ 2014350hI225
49
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

50
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
  • Doans Pills, DeWitts, Momentum - OTC

51
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.

52
Self-Assessment Question
  • The first NSAIDs was and still is?
  • A. Ibuprofen (Motrin)
  • B. Indomethacin (Indocin)
  • C. Acetylsalicylic acid (Aspirin)
  • D. Acetaminophen (Tylenol)

53
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

54
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

55
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)

56
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)

57
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)

58
Longest-Acting NSAIDs
  • Diclofenac (Voltaren XR)
  • Oxaprozin (Daypro)
  • Nalbumetone (Relafen)
  • Etodolac (Lodine XL)
  • Ketoprofen (Oruvail)

59
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)

60
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
  • 1 drop QID
  • 2.5 ml (12), 5 ml (20)
  • Flurbiprofen (Ocufen, generic) 0.03
  • 2.5 ml (12)

61
Where I-NSAIDs are used!
  • Allergic conjunctivitis
  • Eye irritation
  • Dry eyes
  • Analgesia
  • Post-op inflammation due to cataract surgery

62
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
  • Indicated in post-op inflammation due to cataract
    surgery
  • 1 drop three times a day
  • 3 ml suspension (175)

63
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

64
Unique NSAID Formulations
  • Diclofenac Sodium (Solaraze)
  • Actinic keratoses, twice daily for 60-90 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

65
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

66
Other Topical Ideas with NSAIDs
  • Get these through compounding pharmacies
  • Sports injury formula
  • Diclofenac 3, Baclofen 2
  • Diclofenac 3, Baclofen 2, cyclobenzaprine 2,
    gabapentin 6, bupivacaine 2
  • Neuropathic pain formulas
  • Ibuprofen, baclofen 2, amitryptyline 4,
    lidocaine
  • Other formulas have flurbiprofen 10 or
    ketoprofen 10 or ketorolac 0.5 as NSAIDs
  • Moss Goose Grease Gabapentin 5, ketoprofen
    10, lidocaine 5
  • / ketamine 2

67
The STEPS Approach
  • Safety
  • Tolerability
  • Efficacy
  • Price
  • Simplicity

68
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

69
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, lt1, raise SCr
  • Hepatotoxicity
  • Safety
  • Hepatic necrosis and hepatitis are VERY rare

70
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 NSAIDs compared to those who
    dont!
  • Ibuprofen RR 2.0 (0.3)
  • Diclofenac RR 3.7 (0.6)
  • Indomethacin RR 7.2 (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
71
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

72
Prevention of NSAID-induced ulcers
  • Misoprostol
  • 200 mcg TID optimal dose (Ann Intern Med
    1995123241-9)
  • Any GI complication - ARR 0.6, NNT 167
  • Serious upper GI - ARR 0.38, NNT 263
  • 40 will experience diarrhea, NNH 17
  • H2-blockers
  • PPIs
  • ASTRONAUT Trial (N Engl J Med 1998338(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.

73
Chan Studies
  • Study 1
  • 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 cant 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 20023472104-10
74
Chan Study 2 Results
Esomeprazole dose used in the trial was 20 mg
twice daily
Lancet 20073691621-6 (May 12)
75
Renal Effects of NSAIDs
  • Incidence lt 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

76
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 RCTs 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 201330(3)247-55
77
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

78
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-2s 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
79
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 1.59-1.84)
  • 19 more CV events for every 1000 patients treated
  • Diclofenac had a somewhat higher risk
  • Naproxen had a somewhat lower risk

Circulation 2012126(16)1955-1963
80
Vascular Risk Meta-Analysis
  • 280 placebo trials, n 120,000
  • 470 NSAID comparator trials, n 230,000
  • Most trials lasted lt 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 0.3 250
Lancet, online publication, May 30, 2013
81
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
82
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 20144e004059
83
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 2012345e6226
  • 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

84
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
85
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

86
Tramadol CIV
  • Binary analgesic
  • Weak opioid SNRI
  • Drug interactions
  • Seizure risk
  • Those on SSRIs/SNRIs/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)

87
Tramadol CIV
  • Most common side effects
  • 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)

88
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

89
Buprenorphine (Butrans)
  • Efficacy
  • N5,415 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

90
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

91
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

92
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

93
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

94
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95
New for Pain
  • Hydrocodone extended-release
  • 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

96
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

97
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

98
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

99
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

100
Multipurpose Adjuvant Analgesics
  • Tricyclic antidepressant drugs
  • Corticosteroids
  • Anticonvulsants
  • Calcitonin
  • Bisphosphonates
  • Lidoderm
  • Capsaicin
  • Qutenza topical Rx patch for postherpetic
    neuralgia

101
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 20071051805-15
102
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

103
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

104
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 - 300 mg 1-3 hrs before bedtime

105
Pregabalin (Lyrica)
Efficacy
Indication Number of trials NNT
Diabetic neuropathy 3 4
Postherpetic neuralgia 3 3-6
Fibromyalgia 3 Superior to placebo at 8 wks Added to celecoxib is more effective than either alone
Refractory neuropathy 1 5 for gt30 reduction in pain

Anesth Analg 20071051805-15
106
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