THE RIGHT (AND WRONG) WAY TO TREAT PAIN - II ANALGESICS Géza T. Terézhalmy, D.D.S., M.A. Professor and Dean Emeritus School of Dental Medicine Case Western Reserve University Cleveland, Ohio [email protected]

The Right and Wrong Way to Treat Pain “Pain is prefect misery …excessive… overturns all patience.” Marcel Proust 4/16/2013

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The Right and Wrong Way to Treat Pain Pain is an unpleasant sensory an emotional experience…

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The Right and Wrong Way to Treat Pain

…associated with actual or potential tissue damage.

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The Right and Wrong Way to Treat Pain

 Nociception (pain perception)  Sensory detection, transduction, and neuronal

transmission of noxious events

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The Right and Wrong Way to Treat Pain



Stimuli that activate nociceptors (pain receptors)   

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Mechanical Thermal Chemical (algogenic substances)

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

Primary neurotransmitter 

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Glutamate

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The Right and Wrong Way to Treat Pain

 A-delta fibers - myelinated  Connect directly to the thalamus  Synapse with fibers that project to the primary somatosensory cortex

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  

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Information arrives rapidly Sharp, bright, well-localized pain Not particularly persistent  Immediately associated with tissue damage

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The Right and Wrong Way to Treat Pain

 C fibers - unmyelinated  Project to the trigeminal nucleus 

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Reticular formation  midbrain  periaqeaductal gray  hypothalamus  thalamus  cortex

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The Right and Wrong Way to Treat Pain

  

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Information arrives slowly Burning, aching, dull, poorly localized pain Persistent  Provokes suprasegmental reflexes

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The Right and Wrong Way to Treat Pain

 Intrinsic modulation of nociception  Amplification  Macrophages and other immunocompetent cells trigger inflammation 

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Prostaglandin synthesis

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

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Activation of motor and sympathetic reflexes

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 Inhibition  Activity in large myelinated fibers 

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Modulates small-fiber transmission by activating inhibitory cells in the trigeminal nucleus

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

Central control systems 

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Efferent fibers to the trigeminal nucleus inhibit impulses to suprasegmental areas

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 Perception  Awareness of a noxious sensation

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 Interpretation  Attribution of meaning to the experience  Alter or modulate the intensity of a patient’s response to noxious stimuli 

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Cultural, emotional, and motivational differences

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The Right and Wrong Way to Treat Pain  Clinical

manifestations  Loss of function  Excessive rest  Social withdrawal  Demand for

intervention

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The Right and Wrong Way to Treat Pain

ANALGESICS

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The Right and Wrong Way to Treat Pain (analgesics)

Specific inhibitors of pain pathways.

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The Right and Wrong Way to Treat Pain (analgesics)

 Nonsteroidal antiinflammatory drugs  Mechanism of action  Inhibit cyclooxygenase 1 (COX-1) and 2 (COX-2) activity, i.e., the synthesis of prostanoids  

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COX-1 expressed in most tissues - including platelets COX-2 expressed primarily in the brain and kidneys  Induced in all tissues by injury - not found in platelets

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 Acetylsalicylic acid

(OTC) 

Aspirin, Anacin, others 



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Usual analgesic dose  325-650 mg Dose interval  q4-6h

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The Right and Wrong Way to Treat Pain (analgesics)

 Ibuprofen (OTC)  Advil, Nuprin, others 



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Usual analgesic dose  200-400 mg Dose interval  q4-6h

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The Right and Wrong Way to Treat Pain (analgesics)

 Naproxen sodium

(OTC) 

Aleve, others 



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Usual analgesic dose  220 or 440 mg initial, then 220 mg Dose interval  q8-12h

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The Right and Wrong Way to Treat Pain (analgesics)

 Ibuprofen (Rx)  Motrin, others 



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Usual analgesic dose  400-800 mg Dose interval  q4-8h

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The Right and Wrong Way to Treat Pain (analgesics)

 Naproxen (Rx)  Naprosyn, others 



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Usual analgesic dose  500 mg initial, then 250 mg OR  500 mg Dose interval  q6-8h OR q12h

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The Right and Wrong Way to Treat Pain (analgesics)

 Naproxen sodium

(Rx) 

Anaprox, others 



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Usual analgesic dose  550 mg initial, then 275 mg OR  550 mg Dose interval  q6-8h OR q12h 28

The Right and Wrong Way to Treat Pain (analgesics)

 Aniline analgesics  Acetaminophen  Mechanism of action 

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Inhibits an isoenzyme of COX-1 in the brain  Antipyretic effect

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The Right and Wrong Way to Treat Pain (analgesics)



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Acts as a prodrug for N-arachidonoyl-phenolamine that indirectly activates CB1 receptors  Analgesic effect

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The Right and Wrong Way to Treat Pain (analgesics)

 Acetaminophen

(OTC) 

Tylenol, others 



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Usual analgesic dose  500-1000 mg Dose interval  q4-6h

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The Right and Wrong Way to Treat Pain (analgesics)

 Opioid receptor agonists  Mechanism of action  Mu-opioid receptor agonists 

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Inhibition of neurotransmission  Analgesia, euphoria,  respiration

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The Right and Wrong Way to Treat Pain (analgesics)

 Codeine  Weak full agonist 



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Usual analgesic dose  15-60 mg Duration of action  4 hours



Codeine formulations 

w/ASA (Empirin 3)  325/30

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The Right and Wrong Way to Treat Pain (analgesics)



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w/APAP (Tylenol no. 3, others)  30/500

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The Right and Wrong Way to Treat Pain (analgesics)

 Hydrocodone  Weak full agonist 



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Usual analgesic dose  5-10 mg Duration of action  4 hours



Hydrocodone formulations 

w/APAP (Vicodin, others)  5/500

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

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w/ibuprofen (Vicoprofen, others)  5/200

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The Right and Wrong Way to Treat Pain (analgesics)

 Oxycodone  Strong full agonist 



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Usual analgesic dose  5-10 mg Duration of action  4-6 hrs



Oxycodone formulations 



w/ASA (Percodan, others)  5/325 w/APAP (Percocet, others)  5/500

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The Right and Wrong Way to Treat Pain (analgesics)



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w/ibuprofen (Combunox)  5/400

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The Right and Wrong Way to Treat Pain (analgesics)

 Tramadol  Weak opioid receptor agonist/norepinephrine and serotonin reuptake inhibitor 



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Usual analgesic dose  50-100 mg Duration of action  4-6 hrs

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The Right and Wrong Way to Treat Pain (analgesics)

 Tramadol

formulations 



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Plain (Ultram)  50 mg w/APAP (Ultracet, others)  37.5/325

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The Right and Wrong Way to Treat Pain (analgesics)

 Tapentadol  Weak opioid receptor agonist/serotonin reuptake inhibitor 



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Usual analgesic dose  50-100 mg Duration of action  4-6 hrs

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The Right and Wrong Way to Treat Pain (analgesics)

 Tapentadol formulations  Plain (Nucynta)  50 mg

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Cooper SA. Compend Contin Educ Dent 1986;7(8):578, 580-581, 584-588. 4/16/2013

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The Right and Wrong Way to Treat Pain (analgesics)

Cooper SA. Compend Contin Educ Dent 1986;7(8):578, 580-5811, 584-588. 4/16/2013

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The Right and Wrong Way to Treat Pain (analgesics)

Cooper SA. Compend Contin Educ Dent 1986;7(8):578, 580-581, 584-588. 4/16/2013

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The Right and Wrong Way to Treat Pain (analgesics)

Cooper SA. Compend Contin Educ Dent 1986;7(8):578, 580-581, 584-588. 4/16/2013

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The Right and Wrong Way to Treat Pain (analgesics)

Wideman GL, et al. Clin Pharmacol Ther 1999;65:66-76. 4/16/2013

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The Right and Wrong Way to Treat Pain (analgesics)

Wideman GL, et al. Clin Pharmacol Ther 1999;65:66-76. 4/16/2013

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The Right and Wrong Way to Treat Pain (analgesics)

Van dyke T, et al. Clin Ther 2004;26:2003-2014. 4/16/2013

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The Right and Wrong Way to Treat Pain (analgesics)

Litkowski LJ, et al. Clin Pharmacol Ther 1999;65:66-76 . 4/16/2013

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The Right and Wrong Way to Treat Pain (analgesics)

McQuay HJ, Moore RA. An evidence-based resource for pain relief. Oxford, Oxford Univeristy Press, 1998. 4/16/2013

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The Right and Wrong Way to Treat Pain (analgesics)

McQuay HJ, Moore RA. An evidence-based resource for pain relief. Oxford, Oxford Univeristy Press, 1998. 4/16/2013

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The Right and Wrong Way to Treat Pain (analgesics)

A highly popular prescription for the management of moderate to severe odontogenic pain Rx

Tylenol with codeine # 3 tablets Disp: Twenty four (24) tablets Sig. Take 1 or 2 tablets every 4-6 hours as needed for relief of pain It has a number significant problems!

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The Right and Wrong Way to Treat Pain (analgesics)

 Primary line of treatment - mild pain  OTC

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

Ibuprofen (Advil, others), 200-mg tabs, 2 tabs q4h



Naproxen sodium (Aleve, others), 220-mg tabs, 2 tabs q8h



APAP (Tylenol, others), 500-mg tabs, 2 tabs q6h

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The Right and Wrong Way to Treat Pain (analgesics)

 Secondary line of treatment - moderate pain 

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ℜχ Ibuprofen, 400-mg tabs Disp. 20 tabs Sig. Take 1 tab q4h until all are taken OR Take 2 tab q8h until all are taken

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The Right and Wrong Way to Treat Pain (analgesics)

Minutello JS, Newell DH, Thrash WJ, Terezhalmy GT. Evaluation of preoperative diflunisal for postoperative pain following periodontal surgery. J Periodontol 1988 Jun;59(6):390-393. 4/16/2013

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The Right and Wrong Way to Treat Pain (analgesics)

Minutello JS, Newell DH, Thrash WJ, Terezhalmy GT. Evaluation of preoperative diflunisal for postoperative pain following periodontal surgery. J Periodontol 1988 Jun;59(6):390-393. 4/16/2013

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The Right and Wrong Way to Treat Pain (analgesics)

Minutello JS, Hewell DH, Thrash WJ, Terezhalmy GT. Evaluation of postoperative diflunisal for periodontal surgery pain. Am J Dent 1991 Feb;4(1):33-36. 4/16/2013

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The Right and Wrong Way to Treat Pain (analgesics)

Cooper SA. Compend Contin Educ Dent. 1986 Sep;7(8):578, 580-581, 584-588 . 4/16/2013

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The Right and Wrong Way to Treat Pain (analgesics)



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ℜχ Naproxen, 250 mg tabs Disp. 10 tabs Sig. Take 2 tabs stat then 1 tab q6h until all are taken OR Take 2 tabs stat then 2 tab q12h until all are taken

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The Right and Wrong Way to Treat Pain (analgesics)



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ℜχ Naproxen sodium, 275 mg tabs Disp. 10 tabs Sig. Take 2 tabs stat then 1 tab q6h until all are taken OR Take 2 tabs stat then 2 tab q12h until all are taken

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The Right and Wrong Way to Treat Pain (analgesics)



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ℜχ Hydrocodone w/ibuprofen, 5.0 mg/200 mg tabs Disp. 24 tabs Sig. Take 2 tabs q4h until all are taken

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The Right and Wrong Way to Treat Pain (analgesics)



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ℜχ Hydrocodone w/APAP, 5.0 mg/500 mg tabs Disp. 24 tabs Sig. Take 2 tabs q4h until all are taken

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The Right and Wrong Way to Treat Pain (analgesics)



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ℜχ Codeine w/APAP, 30 mg/300 mg tabs Disp. 24 tabs Sig. Take 2 tabs q4h until all are taken

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The Right and Wrong Way to Treat Pain (analgesics)



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ℜχ Tramadol w/APAP, 37.5 mg/325 mg tabs Disp. 24 tabs Sig. Take 2 tabs q4h until all are taken

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The Right and Wrong Way to Treat Pain (analgesics)

 Tertiary line of treatment - severe pain 

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ℜχ Oxycodone w/ibuprofen, 5 mg/400 mg tabs Disp. 24 tabs Sig. Take 2 tabs q6h until all are taken

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The Right and Wrong Way to Treat Pain (analgesics)



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ℜχ Oxycodone w/APAP, 5.0 mg/500 mg tabs Disp. 24 tabs Sig. Take 2 tabs q6h until all are taken

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The Right and Wrong Way to Treat Pain (analgesics)

 Adverse drug events  COX-2 inhibitor - celecoxib (Celebrex)

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The Right and Wrong Way to Treat Pain (analgesics)

 NSAIDs 

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Intolerance

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The Right and Wrong Way to Treat Pain (analgesics)



Gastropathy  

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Direct gastric epithelial cell damage Decreased prostaglandin synthesis   gastric acid secretion   bicarbonate secretion   mucus secretion   blood flow

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

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Anti-thrombotic effects

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The Right and Wrong Way to Treat Pain (analgesics)



Renal toxicity 



Hepatotoxicity 



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 renal prostaglandin synthesis NSAIDs  Idiosyncratic APAP  Dose-dependent

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The Right and Wrong Way to Treat Pain (analgesics)

 Opioid-receptor

agonists   

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Drowsiness Euphoria Dysphoria



Intolerance 



Histamine release

Gastropathy 

Constipation

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The Right and Wrong Way to Treat Pain (analgesics)





Orthostatic hypotension  oxygen consumption

 





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 sensitivity to CO2 Tolerance Miosis

Dependence

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The Right and Wrong Way to Treat Pain (analgesics)

 Adjuvant medications for acute main  Caffeine, 65-200 mg  w/acetaminophen, acetylsalicylic acid, and ibuprofen 

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May enhance analgesic effect

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The Right and Wrong Way to Treat Pain (analgesics)

 Hydroxyzine, 25-50 mg  w/opioids  

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Enhances effect of opioids in postoperative pain Reduces the incidence of nausea and vomiting

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The Right and Wrong Way to Treat Pain (analgesics)

 Corticosteroids  Can produce analgesia in some patients with inflammatory diseases

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The Right and Wrong Way to Treat Pain (analgesics)

 Adjuvant medications for chronic pain  Antidepressants (amitriptyline, nortriptyline, imipramine, venlafaxine, duloxetine, and milnacipran) 

Neuropathic pain syndromes    

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Postherpetic neuralgia Diabetic neuropathy Fibromyalgia Polyneuropathy 78

The Right and Wrong Way to Treat Pain (analgesics)

 Anticonvulsants (gabapentin, pregabalin, carbamazepine, oxcarbazepine, lamotrigine) 

Neuropathic pain syndromes     

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Postherpetic neuralgia Diabetic neuropathy Fibromyalgia Polyneuropathy Trigeminal neuralgia 79

The Right and Wrong Way to Treat Pain (analgesics)

GUIDELINES FOR THE RATIONAL USE OF ANALGESICS IN DENTAL PRACTICE

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START WITH A SPECIFIC DRUG FOR A SPECIFIC TYPE OF PAIN Fully access the patient’s current neurological and psychological status as well as previous analgesic therapies before selecting a medication. 4/16/2013

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The Right and Wrong Way to Treat Pain (analgesics)

RESPECT INDIVIDUAL DIFFERENCES AMONG PATIENTS Drug metabolism can differ widely and side effects reported should not be viewed as psychological since they generally have a pharmacological basis. 4/16/2013

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The Right and Wrong Way to Treat Pain (analgesics)

USE A COMBINATION OF MEDICATIONS Add various non-opioid analgesics when using opioid combinations to enhance analgesia without increasing the dose of the opioid. 4/16/2013

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The Right and Wrong Way to Treat Pain (analgesics)

KNOW THE PHARMACOLOGY OF THE MEDICATION PRESCRIBED Onset, peak, and duration of analgesic action and maximum safe dosages vary with drugs.

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ADMINISTER ANALGESICS REGULARLY Around-the-clock administration has positive pharmacological and psychological effects on the patient.

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TREAT SIDE EFFECTS APPROPRIATELY Side effects such as sedation, nausea, and vomiting should be carefully watched for and the dosage adjusted or symptomatic therapy initiated. 4/16/2013

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WATCH FOR DEVELOPMENT OF TOLERANCE Increasing dosage and frequency of administration or switching to an alternate medication may be necessary to maintain analgesic effect. 4/16/2013

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PAIN DOES NOT ENOBLE! GIVE DOSE ENOUGH SOON ENOUGH OFTEN ENOUGH LONG ENOUGH

GIVE AS YOU WOULD RECEIVE! 4/16/2013

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The Right and Wrong Way to Treat Pain (analgesics) References 1. Abramowicz M. ed. Drugs for pain. Treatment Guidelines from the

Medical Letter. 2010;8(92):25-34. 2. Cooper SA. The relative efficacy of ibuprofen in dental pain. Compend Contin Educ Dent 1986;VII(8):579-581, 584-597. 3. Hersh EV, Golubic S, Moore PA. Analgesic Update: tapentadol hydrochloride. Compend Contin Educ Dent 2010;31(8):594-599 4. Huber MA, Terezhalmy GT. The use of COX-2 inhibitors for acute dental pain. JADA 2006;137:480-487.

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5.

6.

Pickett FA, Terezhalmy GT. LWW’s Dental Drug Reference with Clinical Implications. 2nd ed. Baltimore: Wolters Kluwer Health / Lippincott Williams & Wilkins, 2009. Van Dyke T, Litkowski LJ, Kiersch TA, Zarringhalam NM, et al. Combination oxycodone 5 mg/ibuprofen 400 mg for the treatment of postoperative pain: a double-blind, placebo- and active-controlled parallel-group study. Clin Ther 2004;26:2003-2014.

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