Transcript available now - Grand Strand Advanced Practice Nurse Association

A Comprehensive
Review of
Medications to Treat
Pain
Kelly W. Jones, Pharm.D., BCPS
McLeod Family Medicine Center
[email protected]
Grand Strand Advanced Practice
Nurses Association
1
4/10/2017
Disclaimer
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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
1.
2.
3.
4.
5.
6.
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
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“Controlled Substance" - any drug or substance which is
subject to or has the potential for abuse or dependence
(physical or psychological)
Controlled Substance Act
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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
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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®)
10
Schedule 1
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Schedule 1
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High abuse potential
No current accepted medical use
Usually no safety data
Drugs
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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
CI
Schedule 2
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The medication has a high potential for abuse
High reward
Fast onset
Abuse leads to dependence
Safety and efficacy are known
Medications
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67 listed medications
Cocaine
Most Opioids
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Codeine (as single agent), morphine, etc
Amphetamines
Barbiturates
CII
Schedule 3
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Less abuse potential than CI or CII
Slower onset
Less Reward
Safety and efficacy are known
Medications
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104 listed medications
Opioids: codeine combinations, buprenorphine
Butalbital
Secobarbital in suppository form
Anabolic steroids
Schedule 4
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CIV
Even lower abuse potential than CI to CIII
Slower onset
Less Reward
Safety and efficacy are known
Medications
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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
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CV
Lowest abuse potential
Many of these meds were noted to cause euphoria in
clinical trials
There is limited dependence
Medications
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10 listed medications
Codeine syrup preps (Robitussin AC®)
Diphenoxylate (Lomotil®)
Ezogabine (Potiga®)
Lacosamide (Vimpat®)
Pregabalin (Lyrica®)
New Rule

December 19, 2007
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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
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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
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Phoning
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For a CII emergency
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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
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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
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May be refilled no sooner than 48 hours
CII
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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
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Total Population: 1,280,489
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Practitioner
Mid-Level Practitioner
Pharmacy
Hospital/Clinic
Manufacturer
Distributor
Researcher
Dog Handlers
Analytical Labs
Importer
Exporter
Narcotic Treatment Program
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20
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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.
DHEC Registrants
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Pharmacies
Physicians
Dentists
Veterinarians
Optometrists
NPs
PAs
Hospitals/Clinics
Others
Total
1,077
10,774
2,032
868
360
936
210
491
415
17,163
Harling, Wilbur. “Controlled Substances Regulatory Update." SC College of Pharmacy – USC Campus PHRM 446. 17 Apr. 2008.
21
DEA Numbers
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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’.
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Midlevel practitioners registration numbers begin with an ‘M’
Second letter is the first letter of practitioner’s last name
Examples:
22
AB 1234563
BS 4273102
MJ 3614511
Checking DEA Number
BB1234563
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Add 1st, 3rd, 5th Digits together
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Add 2nd, 4th, 6th Digits & Multiply by 2
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(2 + 4 + 6) 2 = 24
Add both sums together
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1+3+5=9
9 + 24 = 33
Last digit of sum same as DEA last digit
23
Which of the following digits would make this DEA
number an authentic one:
BC445987__
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A.
B.
C.
D.
E.
6
7
8
9
0
4 + 5 + 8 = 17
4 + 9 + 7 = 20 X 2 = 40
17 + 40 = 57
Answer: B = 7
24
25
Chronic Pain is Complex
Patient “A”Pain 8/10
Cultural
Background
Environmental
Stressors
Functional
Disability
Physical
Injury
Social
Disability
Genetics
Cognitive
Dysfunction
Depression
& Anxiety
With permission, SCOPE of Pain, 2015
Patient “B” Pain 8/10
Cultural
Background
Environmental
Stressors
Functional
Disability
Social
Disability
Physical
Injury
Genetics
Substance Use
Depression
& Anxiety
Gatchel RJ. Am Psychol. 2004 Nov;59(8):795-805.
Psychiatric Co-Morbidities
Condition
Prevalence
Chronic Pain Patients
Depression
33 - 54%
Anxiety
Disorders
Personality
Disorders
PTSD
Substance
Use
Disorders
16.5 - 50%
31 - 81%
49% veterans
2% civilians
References
Cheatle M, Gallagher R, 2006
Dersh J, et al., 2002
Knaster P, et al., 2012
Cheatle M, Gallagher R, 2006
Polatin PB, et al. 1992
Fischer-Kern M, et al., 2011
Otis, J, et al., 2010
Knaster P, et al., 2012
Polatin PB, et al. 1992
15 - 28%
Cheatle M, Gallagher R, 2006
With permission, SCOPE of Pain, 2015
Multidimensional Care
Exercise
Manual therapies
Orthotics
TENS
Other modalities
(heat, cold, stretch)
Restore
Function
Physical
Cultivate
Well-being
NSAIDS
Anticonvulsants
Antidepressants
Topical agents
Opioids
Others
It’s More Than Medications
Psychobehavioral
Reduce
Pain
SELF
CARE
Medication Procedural
TENS Transcutaneous Electrical Nerve Stim
CBT Cognitive Behavioral Therapy
ACT Acceptance and Commitment Therapy
Improve
Quality of
Life
CBT/ACT
Tx mood/trauma issues
Address substances
Meditation
Nerve blocks
Steroid injections
Trigger point
injections
Stimulators
Pumps
With permission, SCOPE of Pain, 2015
Things we can do!
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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?
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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?
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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
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“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)
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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
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Butalbital preps
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Fiorinal®, Fioricet®, Sedapap®, Phrenilin®
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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
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34
Alka-Seltzer®,Goody Powder
Butalbital
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FDA indications
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Anxiety about preoperative treatment
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Tension-type headache
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Used as a sleeper the evening before surgery
No benefit over placebo for anxiety the next morning or number of
nighttime awakenings
50-100 mg q4h prn (do not exceed 300 mg/day)
Reduce dose in renal patients – lots of metabolites
Adverse events
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Dependence and addiction
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Dose and duration dependent
Withdrawal can be serious – seizures, hallucination, anxiety
Butalbital – all generic
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Product Grid - butalbital/acetaminophen or
aspirin/caffeine/codeine
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Fiorinal® - 50/325 aspirin/40 mg
Fiorinal with Codeine® - 50/300/40/30 mg
Fioricet® - 50/325 (or 300 mg)/40 mg (capsule)
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Fioricet with Codeine® - 50/300/40/30 mg
Butalbital/acetaminophen – 50 mg/325 mg
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Many other trade names: Esgic® (tab), Zebutal®, Dolgic®, Margesic®,
Vanatol LQ (liquid - 50/325/40 mg per 15 ml
Marten-Tab®, Promacet®, Orviban CF®
Butalbital/acetaminophen – 50 mg/650 mg
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Bupap®, Phrenilin Forte®, Tencon®
Margin of Safety
Margin of Safety
Anesth Prog 2007;54:118-129
Carisoprodol
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Skeletal muscle relaxant
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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
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CIV
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
Added isopropyl group
Carisoprodol
Meprobamate
Carisoprodol Abuse
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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
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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
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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
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Specialty approved patients can be approved for use
European Union members have discussed it
Alabama was the first state to control it (1998)
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18 other states joined in 2011
DEA classification to CIV in all states in 2012
SMJ 2012;105(11):619-23
Morphine
Pain Ladder
Oxycodone or
Oxymorphone
Hydrocodone or combo
Tylenol #3 + NSAID
Tylenol #3 or Tramadol or buprenorphine
NSAID + Acetaminophen
NSAIDs
Acetaminophen or nonacetylated salicylates
43
Nonpharmacologic Approaches
Pain Ladder
Fentanyl
Hydromorphone
Ladder Extension
44
Nonpharmacologic Approach
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Comprehensive therapy with many approaches
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45
Spiritual advise
Rest
Exercise
Biofeedback or Psychotherapy
Heat/cool packs
Hot baths
Complementary medicine
Acetaminophen/APAP/Paracetamol
or just Tylenol®
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Analgesic
No more than 4 grams per day
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Extra strength = 500 mg
5 grains = 325 mg
Caution in alcoholics and those with liver disease
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Or 2600 mg 4 times a day - FDA
2 grams/day limit
Caution with warfarin
Drug of choice for OA??????
46
Acetaminophen is in the NEWS
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Prescription acetaminophen products are limited to 325 mg
per dose
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New 160 mg/5 ml concentration liquid for infants and
children, will contain oral syringe
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3-year phase in period has concluded
Not affecting OTC acetaminophen at this time
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
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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
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Meta-analysis on acetaminophen for the treatment of low back
pain or osteoarthritis
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Search of 9 databases, Cochrane
13 trials of good quality
Full dose 4 gm/day
Results
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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
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Minimal adverse events
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Statistically significant BUT clinically insignificant effect for immediate or
short-term therapy
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
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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
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Safe in aspirin allergic patients
Salicylate toxicity is possible
Can cause tinnitus
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“Weak” to “no” antiinflammatory effects
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49
No RCTs demonstrating efficacy in chronic pain
Onset of action slower than NSAIDs
Analgesic response is individual
Non-acetylated Salicylates Products
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Diflunisal (Dolobid®)
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Choline magnesium trisalicylate (Trilisate®)
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1000 mg tabs or 500 mg/5 ml liquid
Typical dose is 1500 mg BID or 3,000 mg qhs
Salsalate (Disalcid®)
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500 mg - dose is 2 tabs loading dose, then 1 tab twice daily
Generic price - $1.00 per tablet
500 mg, 750 mg tabs
3 g per day in 2-3 doses
Magnesium Salicylate
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50
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
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The first NSAIDs was and still is?
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A. Ibuprofen (Motrin®)
B. Indomethacin (Indocin®)
C. Acetylsalicylic acid (Aspirin®)
D. Acetaminophen (Tylenol®)
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NSAIDs
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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
53
Traditional NSAIDs
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Ibuprofen (Motrin®, Advil®
Diclofenac sodium (Voltaren®)
Naproxen (Naprosyn® and EC Naprosyn®)
Naproxen sodium (Anaprox®)
Flurbiprofen (Ansaid®)
Etodolac (Lodine®)
Nalbumetone (Relafen®)
Oxaprozin (Daypro®)
Indomethacin (Indocin®)
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Tivorbex® (indomethacin) – new product!
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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
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Ketoprofen (Oruvail®)
Sulindac (Clinoril®)
Fenoprofen (Nalfon®)
Piroxicam (Feldene®)
Meclofenamate (no more Meclomen®, only generic)
Mefenamic Acid (Ponstel®)
Tolmentin (Tolectin®)
Quick-Onset, Short-Acting NSAIDs
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Bromfenac sodium (DuractR)
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Off market
Ketorolac IM or oral (ToradolR)
Diclofenac potassium (CataflamR)
Diclofenac (Zorvolex®) – 18 mg, 35 mg caps
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Solumetrix fine particle technology
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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!
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Presupposition
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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)
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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®)
Cox-2 Inhibitors

Only one COX-2 inhibitor


Celebrex® (now generic)
Off Market



Celecoxib
Rofecoxib
Valdecoxib
Vioxx®
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


LS, 5 ml of 0.4% ($200) - for post-corneal refractive
eye pain
Diclofenac (generic) 0.1%



ml ($20),10 ml ($30)
1 drop QID
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%
 Indicated in post-op inflammation due to cataract surgery
 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


Diclofenac Potassium for Oral Solution (Cambia®)




Dry skin, contact dermatitis, GERD pain
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 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
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


Allergic Reactions

safety and tolerability


can be safety and tolerability


Angioedema to fixed-drug eruptions
Gastrointestinal effects


Somnolence, dizziness – 2-5%
Dyspepsia to gi bleeds
Nephrotoxicity


Safety
Acute renal failure is rare, <1%, raise SCr

Safety
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 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
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




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;347:2104-10
Chan Study #2 Results
Esomeprazole dose used in the trial was 20 mg twice daily
Lancet 2007;369:1621-6 (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.



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:




Incidence 1-4/1000
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 COX2 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 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 2012;126(16):1955-1963
Vascular Risk Meta-Analysis



280 placebo trials, n = 120,000
470 NSAID comparator trials, n = 230,000
Most trials lasted < 1 year
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

We await the PRECISION Trial
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.


Naproxen has always been special in migraine treatment –
added to sumatriptan improves efficacy


BMJ 2012;345:e6226
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
Morphine
Pain Ladder
Oxycodone or
Oxymorphone
Hydrocodone or combo
Tylenol #3 + NSAID
Tylenol #3 or Tramadol or buprenorphine
NSAID + Acetaminophen
NSAIDs
Acetaminophen or nonacetylated salicylates
84
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)


85
325mg/30mg; 325mg/60mg
Tramadol

Binary analgesic


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


CIV
There are similar metabolites
Regular release and extended release products (100 mg, 200
mg, 300 mg)
Combination with acetaminophen (Ultracet®)
86
Tramadol

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



CIV
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®



Oxycodone (Oxecta®)



extended release oxycodone/acetaminophen
7.5 mg/325 mg – 2 tabs every 12 h
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
First non-acetaminophen hydrocodone product
Capsules





Indication: management of pain that requires daily, around-theclock, long-term opioid treatment
It is NOT a “prn” medication
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
97
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


98
Anticonvulsant in a patient with seizures
Antidepressant in a patient with depression
Dosing guidelines




99
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

100
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;105:1805-15
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




Fibromyalgia


75 mg bid, increase to 150 tid in week, max dose is 225 mg bid (450 mg/day)
Postherpetic neuralgia




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
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
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 >30% reduction in
pain
Anesth Analg 2007;105:1805-15
Questions?
LOOKING GOOD!
Email questions to:
[email protected]