Non-Opiate Pain Relievers
David A. Cooke, MD, FACP
Assistant Professor, Department of
Internal Medicine
University of Michigan Health System
Case 1
• 76 year old man with hypertension, CAD, and
extensive knee DJD that interferes with activity.
Limited improvement with PT. Taking aspirin,
metoprolol, and atorvastatin. Which medication
should be tried first?
A) Acetaminophen
B) Celecoxib
C) Duloxetine
D) Tramadol
Case 1
• 76 year old man with hypertension, CAD, and
extensive knee DJD that interferes with activity.
Limited improvement with PT. Taking aspirin,
metoprolol, and atorvastatin. Which medication
should be tried first?
A) Acetaminophen
B) Celecoxib
C) Duloxetine
D) Tramadol
Start with the Basics
• Acetaminophen safest option overall.
• Efficacy of NSAID’s vs. acetaminophen
questionable; NEJM study found equivalent.
• Anti-inflammatory benefits of NSAID’s may be
oversold; primarily analgesics.
• Multiple studies show NSAID’s equivalent to
hydrocodone/APAP for acute dental pain.
Acetaminophen and NSAID Pearls
• COX-2 inhibitors are NOT superior to
nonselective NSAID’s for pain; aspirin use
negates any GI safety advantages. VERY
expensive relative to other NSAID’s.
• Combination of acetaminophen plus NSAID is
superior to either alone; 35% improvement on
average in pain ratings.
• Combinations associated with a higher
bleeding risk.
Acetaminophen and NSAID’s
Caveats:
• Max. 3 grams/day of acetaminophen
– Less for chronic liver disease and heavy drinkers
• Short-term risk of nephrotoxicity with NSAID’s,
but both acetaminophen and NSAID’s can lead
to analgesic nephropathy with long-term use.
Tramadol
• Non-opioid Mu opiate receptor agonist with
SNRI-like activities.
• Similar mechanism to tapentadol (Nucynta®).
• Two for one drug? Clinical relevance of SNRI
properties unclear, but probably small.
• Efficacy comparable to codeine.
Tramadol
• Not an opiate structurally, but functionally an
opiate. No sense in combining with opiates.
• Physical dependence, withdrawal, and
addiction can occur.
• Can precipitate seizures; do not use in
predisposed patients.
• Risk of serotonin syndrome with SSRI’s, SNRI’s,
tricyclics, and triptans.
Case 2:
• 52 year old woman with diabetic neuropathy
complains of constant burning pain in her legs,
interfering with sleep. Which is the best initial
medication choice?
A) Acetaminophen
B) Nortriptyline
C) Gapabentin
D) Duloxetine
Case 2:
• 52 year old woman with diabetic neuropathy
complains of constant burning pain in her legs,
interfering with sleep. Which is the best initial
medication choice?
A) Acetaminophen
B) Nortriptyline
C) Gapabentin
D) Duloxetine
Key Points
• Acetaminophen, NSAID’s, and opiates can be
effective for neuropathic pain, but typically
less so than for other types of pain.
• TCA’s, SNRI’s, and gabapentin/pregabalin are
all effective for neuropathic pain.
• Clinically, TCA’s may be more effective for pain
with a burning quality; first choice here.
Tricyclic Antidepressants
• Mechanism in pain: Multiple receptor
activities; serotonin and norepinephrine
reuptake inhibition likely most important;
alters pain signal transmission in spinal cord.
• Improves sleep quality; may be important.
• Also useful for vascular headaches, smoking
cessation, depression, panic disorder, and
anxiety.
Using Tricyclic Antidepressants
• Don’t use amitryptyline!
• Nortriptyline (least sedating) and doxepin
(more sedating) appear equally effective to
amitriptyline, and are much easier to tolerate.
• Start 10-25 mg QPM; increase by 25 mg every
3-5 days as tolerated; target 25-75 mg QPM.
• May take 6-8 weeks to see maximal effect.
Caveats and Precautions
• Side effects: Sedation and dry mouth; usually
tolerable in 10-50 mg/day range. Weight gain
rarely problematic at low doses.
• Levels elevated by concurrent SSRI/SNRI use
• Potential QT prolongation
• Can precipitate urinary retention
• Use carefully in elderly patients
• May aggravate restless leg syndrome
Case 3:
65 year old male with disabling sciatica pain
radiating down the left leg. Describes pain as
like “electric shocks”. Which medication is the
best empiric choice?
A) Naproxen
B) Nortriptyline
C) Gabapentin
D) Duloxetine
Case 3:
65 year old male with disabling sciatica pain
radiating down the left leg. Describes pain as
like “electric shocks”. Which medication is the
best empiric choice?
A) Naproxen
B) Nortriptyline
C) Gabapentin
D) Duloxetine
Gabapentin and Pregabalin
• Gabapentin (Neurontin®, Horizant®)
• Pregabalin (Lyrica®)
• Mechanism in pain unclear. Bind to α2δ subunit of
calcium channels, reducing glutamate release in
excited afferent pain neurons. Decreases pain
signal transmission.
• Clinically, may be more effective for “electric
shock” type pain sensations.
Gabapentin and Pregabalin
• Gabapentin dosing: Typically start 300 mg
QHS, and titrate up by 300 mg every 3 days.
Divide doses TID.
• Best results seen with 1800-3600 mg/day, but
may see responses at lower doses.
• Pregabalin dosing: Start 50 mg TID, and titrate
every 3-7 days to a target of 100 mg TID; max.
600 mg/day, divided BID-TID.
Gabapentin versus Pregabalin?
• Pregabalin $$$ vs. gabapentin $; is one
better?
• Small number of comparison studies
• Very limited data suggests pregabalin may be
superior to gabapentin for pain, but no
convincing head-to-head trials.
• Patients who fail to respond to one may
respond to the other.
Gabapentin and Pregabalin
• Side Effects: Sedation and cognitive
dysfunction are limiting in some patients. Can
cause peripheral edema. Certain patients may
have appetite stimulation and weight gain.
• Pregabalin is Schedule V; gabapentin is not
scheduled. Addictive behaviors have been
seen with both drugs.
Case 4
• 36 y/o woman with depression and
fibromyalgia. Limited response to fluoxetine,
NSAID’s and hydrocodone/APAP. Which
medication might be most useful?
A) Nortriptyline
B) Pregabalin
C) Duloxetine
D) Start tramadol
Case 4
• 36 y/o woman with depression and
fibromyalgia. Limited response to fluoxetine,
NSAID’s and hydrocodone/APAP. Which
medication might be most useful?
A) Nortriptyline
B) Pregabalin
C) Duloxetine
D) Start tramadol
SNRI’s
• Improve pain through lowering central pain
sensitivity
• Same mechanism as TCA’s???
• Four approved SNRI’s in US:
– Venlafaxine (Effexor®, Effexor XR®)
– Desvenlafaxine (Pristiq®)
– Duloxetine (Cymbalta®)
– Milnacipran (Savella®)
• Are pain benefits a class effect?
SNRI’s
• Almost no direct comparison studies
• Duloxetine FDA approved for diabetic
peripheral neuropathy, fibromyalgia, chronic
musculoskeletal pain. Most data on pain uses.
• Venlafaxine not FDA approved for pain, but
modest data to support efficacy.
• Conflicting data for duloxetine vs. venlafaxine
Which SNRI?
• Milnacipran only approved for fibromyalgia.
• Almost no published data on milnacipran; mostly
studied in fibromyalgia.
• Limited data supports efficacy for milnacipran in
treatment of peripheral neuropathy.
• No data on desvenlafaxine use for pain.
• Bottom line: Most convincing data for duloxetine,
but choice frequently dictated by insurance
coverage.
Case 5:
• 44 year old with fibromyalgia complains of
diffuse, aching pain. 25% improvement in pain
with nortriptyline, but cannot tolerate doses
>25 mg/day. What should you try next?
A) Stop nortriptyline, and start pregabalin.
B) Stop nortriptyline, and start duloxetine.
C) Continue nortriptyline and add duloxetine
D) Continue nortriptyline and add gabapentin
Case 5:
• 44 year old with fibromyalgia complains of
diffuse, aching pain. 25% improvement in pain
with nortriptyline, but cannot tolerate doses
>25 mg/day. What should you try next?
A) Stop nortriptyline, and start pregabalin.
B) Stop nortriptyline, and start duloxetine.
C) Continue nortriptyline and add duloxetine
D) Continue nortriptyline and add gabapentin
Combination Therapies
Modest evidence that combinations are more
effective than single agent therapy.
• One trial showed nortriptyline + gabapentin
more effective than either drug alone.
• One trial did NOT show duloxetine +
pregabalin superior to duloxetine alone.
• No data on combining TCA’s with SNRI’s.
Opiates Plus TCA’s
• One trial did not find morphine + nortriptyline
better than either alone, but saw poor results
with all therapies.
• Another study found that TCA’s significantly
reduced opiate usage in patients on
combination.
• More studies of drug combinations needed.
Case 6
65 year old male with severe pain due to
peripheral neuropathy. Limited improvements
with trials of nortriptyline, gabapentin,
pregabalin, venlafaxine, duloxetine, tramadol,
hydrocodone/APAP, and morphine ER, alone
and in various combinations.
Is this patient simply out of luck?
Other anti-epileptics
•
•
•
•
Carbamazepine
Topiramate
Oxcarbazepine
Valproic acid
• Less data than for other drugs, but possibly
effective. Most studied in neuropathic pain.
Other Anti-Epileptics
• Side effects and risks of toxicity generally
higher than other agents.
• Until better data available, best reserved for
cases where all other options have failed.
Major Take-Home Points
• NSAID’s + acetaminophen is worth a try.
• TCA’s and SNRI’s useful in most forms of pain,
particularly neuropathic pain.
• Gabapentin/pregabalin also helpful, especially
in neuropathic pain.
• Discontinue medications if ineffective, but if
one agent doesn’t work, try another!
• Try (TCA or SNRI) + (gabapentin or pregabalin)
if inadequate results with monotherapy.
Questions???