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Non-Opiate Pain Relievers David A. Cooke, MD, FACP Assistant Professor, Department of Internal Medicine University of Michigan Health System.

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Presentation on theme: "Non-Opiate Pain Relievers David A. Cooke, MD, FACP Assistant Professor, Department of Internal Medicine University of Michigan Health System."— Presentation transcript:

1 Non-Opiate Pain Relievers David A. Cooke, MD, FACP Assistant Professor, Department of Internal Medicine University of Michigan Health System

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3 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

4 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

5 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.

6 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.

7 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.

8 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.

9 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.

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11 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

12 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

13 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.

14 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.

15 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 mg QPM; increase by 25 mg every 3-5 days as tolerated; target mg QPM. May take 6-8 weeks to see maximal effect.

16 Caveats and Precautions Side effects: Sedation and dry mouth; usually tolerable in 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

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18 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

19 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

20 Gabapentin and Pregabalin Gabapentin (Neurontin®, Horizant®) Pregabalin (Lyrica®) Mechanism in pain unclear. Bind to α 2 δ 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.

21 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 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.

22 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.

23 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.

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25 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

26 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

27 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?

28 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

29 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.

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31 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

32 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

33 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.

34 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.

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36 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?

37 Other anti-epileptics Carbamazepine Topiramate Oxcarbazepine Valproic acid Less data than for other drugs, but possibly effective. Most studied in neuropathic pain.

38 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.

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40 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.

41 Questions???


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