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THE CHRONIC PAIN VENDING MACHINE:

Making Rational Choices for Seemingly Irrational Conditions
CAPA Conference
October 28, 2016
Jamie Falk, BScPharm, PharmD
www.bizben.com
OBJECTIVES
1.
Review the principles of rational chronic pain management
with a focus on appropriate goals of care.
2.
Understand the evidence base supporting current non-opioid
armamentarium for the treatment of various pain conditions
including chronic low back pain and neuropathic pain types.
3.
Navigate the potential for benefit, harm, and investment by
patient and clinician that are involved in the decision to trial
pharmacological therapies.
4.
Establish what a realistic care plan looks like, taking into
account the time to effect, how to safely titrate, and when to
consider stopping.
HOW DO WE CHOOSE?
 What does the
patient want?
 What is best for
the patient to
accomplish
realistic goals?
Ideally, these align
DRUG
NON-DRUG
www.bizben.com
PERCEPTIONS & MISCONCEPTIONS OF CHRONIC PAIN
 Patient
 The origin of the pain
can be pinpointed
 My pain problem can be
solved
 A pill can solve my pain
problems
 Feels questioned and
develops strategies to
be perceived as credible
 Clinician
 The origin of the pain is
psychosomatic
 Feels suspicious when:
 Patients benefit from being
ill
 Biomedical explanations do
not match patient’s
experience
 Fear of failure when neither
cure, nor improvement nor
consolation is achieved.
BMC Fam Pract 2011;12:31
CASE 1
 Jack is a 50-ish year old male, lots of sitting for
work, with a cardiac and substance abuse history.
He has long-standing mechanical-type back pain
with sciatica symptoms. He is pushing (hard) for
Percocet and is sporadically over-using Tylenol
#3. Non-pharmacologic measures are being
discussed and we would like to offer him nonopioid medication(s).
RESETTING THE STAGE
 How is the current approach not working for you?
 How might it fail you in the long run?
 What may be a better approach?
…or, is it the improvement of the
overall pain experience?
NEJM 2015;373:2098-99
 “For many patients, especially those who have become
dependent on opioids, maintaining low pain scores requires
continuous or escalating doses of opioids at the expense of
worsening function and QoL.”
 “Over time, pain intensity becomes linked less with
nociception and more with emotional and psychosocial
factors. Suffering may be related as much to the meaning of
pain as to its intensity”
 “Persistent helplessness and hopelessness may be the root
causes of suffering for patients with chronic pain yet be
reflected in a report of high pain intensity”
THE PAIN EXPERIENCE
“A biopsychosocial condition”
https://www.youtube.com/watch?v=4b8oB757DKc
J Prim Health Care 2012;4(3):254-8
RESETTING THE STAGE
 What may be a better approach?
1. What are realistic goals for future care?
“FUNCTION”  what does that mean to this patient
2. How can we try to accomplish those goals?
GOALS OF THERAPY
CHRONIC PAIN
Sleep
ACUTE PAIN
QOL
Sleep
Exercise
 pill burden
Pain reduction
Improved mood
 mobility
 side effects
 cost
 pill burden
Exercise QOL
Pain reduction  cost
Improved mood
 mobility
 side effects
FUNCTIONAL BREAKDOWN:
Assessing the Pain Experience
http://nationalpaincentre.mcmaster.ca/opioid/
 How do we help the patient
accomplish these goals?
NON-PHARMACOLOGICAL THERAPIES FOR CLBP
★
 Evidence for benefit exists for all of the
following:
FREE
 Heat
 Massage
FREE
 Yoga
FREE 
FREE? 


FREE? 
GOAL: MOVE FROM
PASSIVE modalities to
ACTIVE rehabilitation
Exercise
Physiotherapy
Acupuncture
Behavioural therapy
Multidisciplinary programs
PHARMACOLOGICAL THERAPIES
 What pharmacological options do we have for
chronic low back pain?






Muscle relaxant (cyclobenzaprine): IF spasms involved  7-14 days
max
Acetaminophen: likely hasn’t helped this patient; BMJ meta-analysis
(2015) & Cochrane review (2016)  no better than placebo
NSAIDs (oral, not topical)
 NSAID = opioids? (very few not great studies)
TCAs: vs. placebo  equivocal
Gabapentin  if sciatica? Substance abuse concern?
Epidural corticosteroids  if sciatica?
The GOAL: use relatively passive modalities (drugs) to support ACTIVE rehabilitation
A brief NSAID diversion…
NSAIDs: effectiveness
vs. placebo
OA1,2
• NNT (≥50% pain ) = 4-5
Acute Low
Back Pain3
• Similar pain  vs. opioids
• Better vs. acetaminophen for
pain, global improvement, &
function
• Similar pain  vs. acetamin
• -9 points (0-100 pain scale)
• No functional benefit of
adding cyclobenzaprine or
• NNT=10 for global improvement
opioids to naproxen X 1 week
Chronic Low
• -3.3 points (0-100 pain scale)
Back Pain4
• -0.9 points (0-24 disability scale)
1.
2.
3.
4.
vs. other drugs
BMJ 2015;350:h1225
CDSR 2006, Issue 1. Art. No.: CD004257
JAMA 2015;314(15):1572-1580
CDSR 2016, Issue 2. Art. No.: CD012087
• Similar pain  vs. opioids
(based on very few trials)
• One trial showing pain  for
celecoxib vs. tramadol
NSAID HARMS: risk factor considerations
 Renal
 GI


Any one NSAID better than the others?
 not likely
What is the risk?   1.3-2.2 X, but it
depends on…





*
RF:
Volume depletion/diuretics
CHF
ACEI, ARB use
Renal disease, cirrhosis
≥ 70 yoa
Eur J Intern Med 2015;26:285–291 3
 Cardiac

*
(COX-2 inhibitors)


Arch Int Med 2002;162:2105-10
Diclofenac & high-dose celecoxib worst
  risk by 2-4X  <0.5%/yr
Low-dose naproxen (≤750 mg/d), ibuprofen
(≤1200 mg/d), and celecoxib (≤200mg/day)
appear CV “neutral”
Again, absolute risk depends on other
risks…
 CHF , CAD, high risk for CVD
BMJ 2010;342c:c7086, Lancet 2013;382: 769–79, rxfiles.ca
TOPICAL NSAIDs: effectiveness
Advantage: major adverse effects comparable to placebo
(systemic availability = 2-15% vs. oral NSAIDs)
 Osteoarthritis:



=
vs. oral NSAIDs for OA of hands and knees:
vs. placebo for OA, tendonitis (BMJ 2004;329:324-6):
 > 50% pain relief (week 1)  74 vs. 44% (placebo)
 > 50% pain relief (week 2)  92 vs. 58% (placebo)
 > 50% pain relief (week 4)  55 vs. 57% (placebo)
vs. placebo for OA (CDSR 2012, CD007400):
 > 50% pain relief (week 8-12)  NNT = 6.4-11
 No evidence to support topical NSAIDs in back pain,
neuropathic conditions or widespread pain
} NNT = ~3
BACK to JACK: SCIATICA
 20-30% continue to have persistent
pain for 1-2 years or longer
 Sciatica patients are ~ 5X more
likely to use drugs than those
with LBP only
But… sciatica resolves
without treatment in 1/3 of
patients within 2 wks and in
3/4 of patients within 3
months after onset
BMJ 2012;344:e497 doi: 10.1136/bmj.e497
N Engl J Med 2015;372:1240-8.
Evidence for
SCIATICA
therapies
Fig. 5. Plot of the weighted mean difference for pain intensity for different treatment
strategies compared with inactive control from the network meta-analysis.
Spine J 2015;15:1461–1477
Evidence for
SCIATICA
therapies
Fig. 4. Plot of the odds ratios (ORs) of global effect for different treatment strategies
compared with inactive control from the network meta-analysis.
Spine J 2015;15:1461–1477
Evidence for NSAIDs and corticosteroids:
PAIN (on a scale of 0-100)
(2-12 wks)
BMJ 2012;344:e497 doi: 10.1136/bmj.e497
EPIDURAL STEROIDS: chronic LBP
TOP LBP Guideline 2015
Let’s dig a little deeper…
•
•
•
Headache, nausea, dizziness
(accidental puncture of dura mater in
2% - 5%)
Inadvertent intrathecal injection 
neurotoxicity
Infections (rare but serious) 
epidural abscess, meningitis
EPIDURAL STEROIDS: chronic LBP
Instead, perhaps this should read…
For patients who have persistent and disabling sciatica, epidural
corticosteroids are available treatment options with short-term
effects on clinical outcomes that need to be considered in the
shared decision-making process.
- Ann Intern Med 2012;157:865-877
TOP LBP Guideline 2015
Evidence for various drug
therapies: PAIN & DISABILITY
Fig 2: Mean difference for pain and disability in placebo controlled
trials on pain relief in patients with sciatica (0-100).
BMJ 2012;344:e497 doi: 10.1136/bmj.e497
“GABAPENTINOIDS”
 Yildirim (2003)
 n=50 with L5 or S1
radiculopathy
 Gabapentin
900-3600mg/d or
placebo X 8 weeks
 Results:
Mean pain difference
= -26.6 (0-100)
Pain Clinic 2003;15:213-8
Pain 2010;150:420–427
 Baron (2010)
 n=217 with L5 or S1
radiculopathy
 Pregabalin 150-600mg/d
(responders) or placebo
X 5 weeks
 Results: no difference in
time to loss of response
IS THAT THE END OF THE ROAD?
 Or, do we choose to extrapolate (despite a
general lack of evidence in the sciatica literature)
BACK TO JACK’s BACK: CLBP & SCIATICA
GENERAL
 Reset the stage (realistic
goals, active vs. passive, what
lies ahead)
 Find the non-pharm options
that he’s most likely to engage
in then prescribe & monitor
like a drug
 ++ patient engagement in a
drug trial
 Stop any drugs that aren’t
likely helpful or are harmful
SPECIFIC
 Is he a candidate for an oral
NSAID? Has he tried one in the
past? If CV hx  naproxen or
low-dose celecoxib
 Is imaging indicated based on
physical assessment (e.g. MRI
for nerve root impingement)?
 If nerve root issues 
epidural steroid trial?
 Is a gabapentin (or TCA?) trial
reasonable?
CASE 2
 Betty is a 70 year old female with a 1 year hx of
painful diabetic neuropathy which mostly
presents as burning pain in her feet. She’s tried
to manage with OTC pain relievers and creams.
 Other medical history:
 Osteoporosis (compression fracture several
years ago (x-ray proven, not painful))
 OA in both knees
 Depression stable on sertraline 100mg X 1
year with good effect (multiple MDD
episodes in the past)
 Not uncommon to wake up due to pain
How will this
effect our
choice of agent
?
Painful Diabetic
Neuropathy
WEIGHT OF
EVIDENCE for
pain meds BY
NEUROPATHIC
PAIN TYPE
Post-herpetic
Neuralgia
Mixed
Neuropathies
Peripheral Nerve
Injury (e.g. postamputation)
Central Pain (e.g. poststroke, MS, SCI)
HIV Neuropathy
NEUROPATHIC PAIN MEDS: effectiveness
BE WARY OF COMPARING NNTs!
Low quality studies with
potential for major bias 
overestimation of tx effect?
WEIGHT OF
EVIDENCE BY
MEDICATION
TYPE
Pain 2010;150:573–581.
(CDSR, 2015 Issue 1. Art. No.: CD011209
CDSR, 2015 Issue 7. Art. No.: CD008242
CDSR, 2015 Issue 8. Art. No.: CD011091)
Unblinding,
industry bias
(~50% pain relief)
NEUROPATHIC PAIN MEDS: effectiveness
CHOICE DEPENDENT ON:
• Past hx of use
• Comorbidities
• “Preferred” side effects
“Strong”
recommendation
for use
“Weak”
recommendation
for use
Lancet Neurol 2015;162–73
A closer look at DIABETIC NEUROPATHY
Notice the response rates…
HOW SHOULD THIS BE TRANSLATED?
J Diab Comp 2015 (29(1):146-56
WHAT ABOUT FUNCTIONING?
?
Of 26 studies in neuropathic pain showing a meaningful 
in pain, only 11 reported a significant improvement in QoL
Our role in assessing this is +++ important
(what function means to the patient & degree of change)
NEUROPATHIC PAIN MEDS: harms
Medication
“Notable” Side Effects
Cautions
TCAs
Anticholinergic, weight
gain, sedation, orthostatic
hypotension
Elderly, dementia, existing
orthostatic hypotension,
glaucoma, urinary
retention, cardiac disease
Gabapentin,
pregabalin
Dizziness, sedation,
peripheral edema
Elderly, existing edema,
fall risk, abuse potential
SNRIs
Nausea,  BP, dizziness
HTN?, Bipolar disorder
Not covered in MB
Duloxetine = $0.50-$1.00/tablet and only EDS if for diabetic neuropathy or
depression & failed 2 other agents in MB
• Up to 80% experience at least 1 adverse event
• In many trials, the drop-out rate due to side effects is 10-30%
NEUROPATHIC PAIN MEDS:
context
www.ti.ubc.ca Oct 2015
BACK TO BETTY…
 She returns to your clinic 2 weeks after starting
gabapentin for her painful diabetic neuropathy.
She is now at a dose of 200mg TID (you
intentionally took things slowly). She had some
mild dizziness at first, but no longer an issue.
She’s frustrated that this new pill doesn’t work.
 What does a reasonable trial of a
neuropathic pain med look like?
NEUROPATHIC PAIN MEDS: specifics
Dose (mg)
(initial/usual effective/max)
TCAs
Gabapentin
Pregabalin
Duloxetine
Venlafaxine
10-25 HS / 50-100 HS / 150 HS
300 daily / 300-900 TID / 1200 TID
75 BID / 150-300 BID / 300 BID
30 daily / 60 daily / 120 daily
37.5 daily / 150-225 daily / 300 daily
Fast track:  dose by 50-100% q3d
Onse
Adequate
t
trial (wks)
(wks)
≤1
1
1
1
1
Until the low end of
the “usual effective”
dose is reached, then
approach:  dose by 50-100% q1w
Can J Infect Dis Med Microbiol 2010;21:45-52 Lancet Neurol 2010; 9: 807–19
rxfiles.ca
4-6
4-6
4-6
4-6
4-6
PRACTICALITIES: DOSING
 Always start low & go slow
 This is a chronic condition…
1. there is no rush
2. not worth risking harm to the patient
3. side effects may result in loss of a viable option in the mind of the patient
 Higher doses have a low likelihood of resulting in greater
benefit and are more likely to result in greater harm
 Applies as strongly to active non-pharmacological
approaches (e.g. exercise)
NEUROPATHIC PAIN MEDS: topicals
 Lidocaine

5% plaster or patch most
studied  modest benefit in
low quality, short-term trials

 Ointment compounded at

some local pharmacies 
equally effective???
 Applied TID-QID?


 Capsaicin
1st or 2nd-line in several
guidelines for PHN
ADVANTAGE:
 Onset immediate
 Minimal systemic absorption
Drugs Aging 2014;31:853–862
Lancet Neurol 2015;162–73
Pain Res Manag 2014;19:328-35
2012 CDSR for 0.075% gel
(Zostrix HP)  insufficient
data to draw conclusions
8% patch (NNT=11) not
available in Canada
 Ketamine alone

Case series supporting pain
relief vs. placebo
 Amitriptyline +
ketamine


1 trial = oral gabapentin
1 trial = placebo
COMBINATION THERAPY: dynamic duos?
 Studies generally small with some
questionable methodology
 decisions often based on
“logical combinations”


Some combos with some ✚ data:
 Gabapentin + nortriptyline
 Gabapentin + opioid
 ?Lidocaine patch + pregabalin
 Topical amitriptyline + ketamine
PROMISING THEORY:
“Use of 2 agents with
different mechanisms of
action at suboptimal doses
may provide the degree of
synergy necessary for
optimal pain relief without
compromising the sideeffect profile of each agent.”
Several negative trials:
 Pregabalin + opioid, pregabalin + duloxetine, lamotrigine +
gabapentin or non-opioid analgesic, topical amitriptyline + ketamine
CNS Drugs 2011:25:1023-1034
CDSR 2012, Issue 7. Art. No.: CD008943
•
STAYING THE COURSE, ALTERING THE
Inform patients that the
COURSE, OR STARTING OVER?
outcome in many is
favourable even if
symptoms tend to wax
and wane over time
• Caution on coincidences Yes
Side Effects
Tolerable?
No
Benefit at
lower dose?
No
No
Yes
Yes
Continue
and reassess
Functional
benefit?
None
Some
Continue
+/- increase
dose, or, if at
upper dose
+/- add
another agent
If effective… Reassess for ongoing need in 3 months
Increase dose if not
near upper dose
If at upper dose
Stop and switch to
another agent,
patient willing
ENGAGING THE PATIENT
1. You’re likelihood of benefit is ________ (NNT, % response)
2. A reliable benefit is likely to be seen in __________
days/weeks
3. Side effects to watch out for include ____________, and
have an incidence of ________% (or 1 in ____ chance)
4. The approximate cost is _________$ per month and it is/is
not covered by your drug plan
 If there are several reasonable options to choose
from, which would the patient prefer based on this?

 “Although 69 new randomized controlled trials have been
published in the past 5 years compared with 105 published trials
published in the preceding 39 years, only a marginal
improvement in the treatment of the patients with neuropathic
pain has been achieved.”
Finnerup, et al. Pain 2010;150:573–581
And, referring to chronic pain in general…
 “Overall, currently available treatments provide modest
improvements in pain and minimum improvements in physical
and emotional functioning. The quality of evidence is mediocre
and has not improved substantially during the past decade.”
Turk, et al. Lancet 2011 Jun 25;377(9784):2226-35
So…
MULTIMODAL CARE
 “…encompasses behavioral, physical, and
integrated medical approaches. It is not titrated to
pain intensity but has a primary goal of reducing
pain-related distress, disability, and suffering.
When it does that successfully, a reduction in pain
intensity might follow — or acceptance might make
the intensity of pain less important to a person’s
functioning and quality of life.”
ROLE OF THE CLINICIAN/PRESCRIBER:
• Ensure safe and effective medication use
• Move patients away from a drug-centric approach to pain management
• Collaborate with others to reinforce positive approaches
★
NEJM 2015;373:2098-99
PREVENTABLE PATIENT SCENARIOS:
1) ALWAYS WANTING MORE
2) STUCK, BUT NOT KNOWING HOW TO GET FREE
QUESTIONS

[email protected]