Analgesic Combinations

Question 1

Recent Analgesia Changes

Answer 1

Acetaminophen - Prescribed analgesic combos to 325mg/dosage form
Hydrocodone and Acetaminophen combo - Schedule II
Extended release Hydrocodone (Zohydro ER)

Question 2

Opiate VS NSAID

Answer 2

Opiate: Receptors in brain, spinal cord and peripheral nerves (Morphine - No “ceiling dose”, Severe pain; Codeine - “Ceiling = 60mg/dose (360mg/24hr)”)
NSAID: Analgesia by blocking prostaglandin synthesis - Inflammatory mediators, Peripheral and Central inhibition, “Ceiling analgesia”, Doses in combo products the non steroidal agent provides significant analgesia

Question 3

Acetaminophen

Answer 3

Block prostaglandin synthesis in brain but not periphery; Diff side effect profile from other NSAIDs: No ulcers, No block of platelet aggregation (but potentiates anticoagulant warfarin), Not contraindicated in pregnancy, Used in patients with aspirin intolerance, Used in children (no Reyes syndrome), Does not interfere w/ortho adjustment and implant integration, Renal effects differ from NSAID but additive, Overdose results in fatal hepatotoxicity
Ceiling dose - 4000mg/24hr
Severe liver injury - Took more than prescribed dose in 24hr, Took more than one product, Drank alcohol
Single dose = 325mg/dose
Increased analgesia up to 1000mg/dose
Black Box warning for hepatotoxicity
Now recommend of 3000mg/day max
APAP + NSAID INCREASE ANALGESIA BUT ALSO HEPATOTOXICITY AND RENAL TOXICITY - CAFFEINE INCREASES APAP RENAL DAMAGE

Question 4

Analgesic Dosing Limit

Codeine

Answer 4

Dental adult single oral dose - 60mg max

24hr max - 360mg (Determined by side effects)

Question 5

Analgesic Dosing Limit

Hydrocodone

Answer 5

Dental adult single oral dose - 10mg t1/2 = 3-5hrs

PHS recommendations will produce drowsiness

Question 6

Analgesic Dosing Limit

Oxycodone HCl

Answer 6

Dental adult single oral dose - 10mg q4-6hrs

PHS recommendations will produce drowsiness

Question 7

Analgesic Dosing Limit

Meperidine

Answer 7

Not recommended oral

Question 8

Analgesic Dosing Limit

Aspirin

Answer 8

Dental adult single oral dose
1000mg q6h
24hr max - 6000mg
Max for arthritis patients; Dose limited by tinnitus, GI, Platelet effects, Renal effects

Question 9

Analgesic Dosing Limit

Acetaminophen

Answer 9

Dental adult single oral dose
1000mg q6h - FDA recommends 625mg
24hr max - 3000mg; Moderate alcohol 2000mg
Dose limit by hepatotoxicity, McNeill reduced to 3000mg

Question 10

Analgesic Dosing Limit

Ibuprofen

Answer 10

Dental adult single oral dose
400-600mg q6h
24hr max - 3200 mg/day
Dose limit by GI, renal and hepatic toxicity

Question 11

Rationale to Combine Analgesics

Answer 11

Analgesic actions of NSAIDs and Opiates are additive - Act at multiple analgesic sites; Recent evidence - Acetaminophen and NSAID potentiate each other
Opiates combo w/reduced abuse liability compared to pure (Opiates + NSAID/Acetaminophen)
Not useful for chronic pain patients w/tolerance to opiate

Question 12

Mild Pain

Answer 12

Aspirin or Acetaminophen alone

Question 13

Moderate Pain

Answer 13

Mix w/ Acetaminophen or Aspirin and Hydrocodone or Codeine; Some NSAID taken alone - Ibuprofen

Question 14

Severe Pain

Answer 14

Emphasis on stronger opiates, oxycodone, morphine etc; NSAID used but avoid NSAID and APAP toxicity (Ceiling doses), However Ibuprofen/APAP combo relieve dental pain
Use opiates alone at higher doses

Question 15

NSAID Purpose in Combo

Answer 15

Block inflammatory pain, prostaglandin mediated peripherally and centrally (Newer reduce swelling)

Question 16

Acetaminophen Purpose in Combo

Answer 16

Blocks pain w/potency equal to aspirin but inhibit prostaglandin synthesis significantly greater in the brain; Side effects - Diff from ASA or NSAIDs; After dental extractions - Acetaminophen produce somewhat less swelling and bleeding than aspirin

Question 17

Opiates Purpose in Combo

Answer 17

Act centrally (Some peripheral block pain transmission into CNS), Activate Mu (MOP) opiate receptors to block pain, Codeine is partial agonist prodrug that requires CYP2D6 to metabolize to morphine; Morphine, Hydrocodone and Oxycodone act directly on Mu (MOP) receptors, Oxycodone and Hydrocodone are orally active (Oral morphine is 1/3 - 1/4 bioavailable)

Question 18

Tramadol (Ultram)

Answer 18

CIV; Prodrug for M1 metabolite requires CYP2D6 to convert, M1 metabolite more Mu (MOP) potent; Weak reuptake blocking for NE and 5HT (add to analgesia) but major actions are slow in onset - Serotonin syndrome or NE toxicity (Antidepressants block reuptake of NE and 5HT are helpful in chronic pain); Better drug for chronic pain patients not acute dental patients or where NSAID ceilings reached - Use in dental patients is OFF label use; Dose rate every 6hrs is too frequent for active metabolite w/ t1/2 of 7.4hrs, Give every 8-12hrs; Comparative studies w/ other analgesics for treating postop pain indicate tramadol is equivalent in analgesic to codeine (less effective than acetaminophen), codeine and acetaminophen; hydrocodone combo for treat of dental and acute musculoskeletal pain
Tapentadol (CII) (Nucynta) for chronic pain
May result in increase use - Toxicity like arrhythmia and serotonin syndrome

Question 19

NSAID and Occult toxicity

Answer 19

Opiate drowsiness - Overdose
NSAID - GI bleeding, Nephrotoxicity, Bleeding increase; Pushing doses on NSAID lead to delayed and serious clinic problems

Question 20

Patients to use Opiates-APAP combo

Answer 20

Patients not candidates for NSAIDS - Pregnant, Hypertension, Peptic ulcer, Increase risk of heart attack nd stroke w/COX II agent, Adverse bone healing and ortho adjustment problem

Question 21

Analgesic Dosing Limit

Antihistamine/Phenothiazines

Answer 21

Potentiate opiate sedation - Reduce dose of antihistamine and opiate; Antihistamine action blocks effects (H1 receptors) of opiate released histamine such as itching, Anti nausea action reduce opiate induced nausea, Antihistamines said to be mildly analgesic, No evidence that neuroleptics increase analgesia - Agents do increase drowsiness; Opiate + Neuroleptic = Neuroleptanalgesia

Question 22

Analgesic Dosing Limit

Barbiturates

Answer 22

Available in products for migraine pain
Anti-hyperalgesia action - Block AMPA/Kinate receptors; Value in migraine or neuropathic chronic pain

Anticonvulsants (Neuropathic pain) - Carbamazepine, Phenytoin, Valproate etc; Gabapetin (Neurontin) and Pregabalin (Lyrica) used for neuropathic nerve pain based on calcium channel blocking

Question 23

Analgesic Dosing Limit

Stimulants

Answer 23

Caffiene, Amphetamines, Cocaine and Antidepressants
Current pain theory supports use of agents that contain NE increasing stimulants or antidepressant agents
Add to analgesia by augment NE descending inhibitory transmission (alpha2) and by Reducing sedative side effects of opiates, Rational for caffeine not clear - Improves Acetaminophen efficacy but only in headaches - May reduce caffeine withdrawal induced headaches and increase renal toxicity

Question 24

Analgesic Dosing Limit

Sumatriptan+APAP combo

Answer 24

Serotonin agonist helps migraine pain, APAP effective in reducing migraine pain (Combo not a general dental agent)

Question 25

Analgesic Dosing Limit

Buffers

Answer 25

Reduce GI side effect of aspirin but amt of buffer is subtherapeutic; Not rational in Acetaminophen combos or in opiates alone