Pain Therapeutics

Pain Therapeutics Chris Herndon, PharmD, BCPS, CPE, FASHP

Disclosures  Nothing to Disclose  Off-label use of medications will be discussed

Objectives  Identify the most common etiologies of pain syndromes and evidence based practice recommendations when available  Differentiate opioid equianalgesic dosing, side effects, and patient specific monitoring parameters  Identify appropriate patient-specific clinical scenarios in which adjuvant or co-analgesics are appropriate  Construct a treatment plan based on likely known pathophysiologic mechanisms of nociceptive, neuropathic, or sympathetically-maintained pain

Outline  Epidemiology  Nociception in a minute  Opioids, co-analgesics, adjuvant analgesics  Equianalgesia in a minute  Pain syndromes – Chronic low back pain, osteoarthritis, fibromyalgia, cancer pain, postoperative pain, complex regional pain syndrome, central post-stroke pain

 Appropriate monitoring / universal precautions  On the horizon

Age Adjusted Rates Of U.S. Adults Reporting Pain In The Last 3 Months

The Prevalence of Pain is Staggering

CDC and NCHS. 2010. Health. United States, 2010. Chartbook, Special features on death and dying, Hyattsville, MD:CDC and NCHS.

Extent Of Pain-related Disability Among Adults With Pain In The Last 3 Months, United States, 2009

The Disability of Pain is Crippling

CDC and NCHS. 2010. Health. United States, 2010. Chartbook, Special features on death and dying, Hyattsville, MD:CDC and NCHS.

Trends in pain prevalence, United States, 1999-2004

Pain is a Chronic Problem

Institute of Medicine. Relieving pain in America: A blueprint for transforming prevention, care, education, and research. http://www.iom.edu/Reports/2011/Relieving-Pain-in-America-A-Blueprint-for-Transforming-Prevention-Care-Education-Research.aspx. Accessed January 3, 2012.

How Do We Classify Pain?

Pain Nociceptive Somatic

Visceral

Sympathetic

Neuropathic Central

Getting Lost In The Definitions  Addiction  Dependence  Tolerance  Pseudoaddiction  Malingering  Windup  Central Sensitization  Hyperalgesia  Allodynia

any recurrent activity which results in negative outcomes to health, social, or professional relationships. The addicted individual is aware of these outcomes yet continues the activity

Getting Lost In The Definitions (cont’d)  Addiction  Dependence  Tolerance  Pseudoaddiction  Malingering  Windup  Central Sensitization  Hyperalgesia  Allodynia

a physiologic, receptor response to an exogenous substance and the result from removing that substance

Getting Lost In The Definitions (cont’d)  Addiction  Dependence  Tolerance  Pseudoaddiction  Malingering  Windup  Central Sensitization  Hyperalgesia  Allodynia

needing higher doses to elicit the same response (analgesia vs. euphoria)

Getting Lost In The Definitions (cont’d)  Addiction  Dependence  Tolerance  Pseudoaddiction  Malingering  Windup  Central Sensitization  Hyperalgesia  Allodynia

exhibiting aberrant or addicted behaviors due to undertreatment of a legitimate pain syndrome

Getting Lost In The Definitions (cont’d)  Addiction  Dependence  Tolerance  Pseudoaddiction  Malingering  Windup  Central Sensitization  Hyperalgesia  Allodynia

exhibiting aberrant or addicted behaviors or basically “faking it”

Getting Lost In The Definitions (cont’d)  Addiction  Dependence  Tolerance  Pseudoaddiction  Malingering  Windup  Central Sensitization  Hyperalgesia  Allodynia

Appropriate and useful nervous system changes due repetitive stimuli

Getting Lost In The Definitions(cont’d)  Addiction  Dependence  Tolerance  Pseudoaddiction  Malingering  Windup  Central Sensitization  Hyperalgesia  Allodynia

inappropriate and useless nervous system changes due to ongoing, long-term noxious stimuli

Getting Lost In The Definitions (cont’d)  Addiction  Dependence  Tolerance  Pseudoaddiction  Malingering  Windup  Central Sensitization  Hyperalgesia  Allodynia

Heightened painful response to a normally painful stimuli

Getting Lost In The Definitions (cont’d)  Addiction  Dependence  Tolerance  Pseudoaddiction  Malingering  Windup  Central Sensitization  Hyperalgesia  Allodynia

Heightened painful response to a normally non-painful stimuli

Nociception

Transduction Conduction Transmission Modulation Perception

Nociceptors Thermal Mechanical Chemical Silent or Sleeping

Nociception is a complex process

Raouf et al, 2010

Nociception PAG RVM

Excitatory (Chemical) Glutamate Glycine

Neuronal Impulse

SubP H+ CGRP

Dorsal

Na, K, Ca, Îą2a

Horn

Inhibitory (Chemical) GABA NE/SE

Primary Afferent

CCK IL CK

Transmission Primary Afferents

Nociceptive Alpha-Beta

Alpha-delta C-polymodal

First Pain versus Second Pain

Julius D. Nature, 2001.

Ascending and Descending Pathways The Thalamus is the “Pit Crew” (Modulation)

Adapted from Gottschalk A, Smith DS. Am Fam Phys. 2001;63:1979-1986.

Pharmacotherapy (based on a new taxonomy) Drug Class / Mechanism of action

IASP Pharmacology of Pain

Opioids

Antinociceptive

Anticonvulsants

Peripheral desensitization

TCAs

Descending modulator

SNRIs

Descending modulator

Local Anesthetics

Peripheral desensitization

NSAIDs

Antinociceptive

Acetaminophen

Antinociceptive

NMDA antagonists

Antihyperalgesic

Capsaicin

Peripheral desensitization

Cannabinoids

Antinociceptive

Corticosteroids

Peripheral desensitization

Skeletal muscle relaxants

Descending modulator

Beaulieu P, Lussier D, Porreca F, Dickenson AH, editors. Pharmacology of pain. Seattle, WA: International Association for the Study of Pain (IASP) Press; 2010.

Opioids  mu-agonists – Morphine, methadone, codeine, hydrocodone, fentanyl, oxycodone, oxymorphone, levorphanol

 Partial mu-agonists – Buprenorphine, butorphanol

 Mixed agonist-antagonist – Nalbuphine, pentazocine

 Central (mu + NE / 5HT) – Tramadol, tapentadol

Opiate and Opioids  Opium derived from Greek word opos for “juice”  Derived from the juice of the opium poppy Papaver somniferum  20 different distinct naturally occurring alkaloids  Opiates are naturally occurring products and semi-synthetic derivatives  Opioids are all compounds related to opium  Narcotic is the Greek word for “stupor”

Milking The Poppy

This Is What It Looks Like After‌

http://www.uwmc.uwc.edu/political_science/opiumprod.html. Accessed June 14, 2012.

How Much Do We Use?

Report of the International Narcotics Control Board on the Availability of Internationally Controlled Drugs: Ensuring Adequate Access for Medical and Scientific Purposes. http://www.incb.org/incb/en/annual-report-2011.html. Accessed June 14, 2012.

Opioid Receptors and Actions Effect Analgesia

Receptor

Agonist

Antagonist

Mu, kappa, delta

Analgesia

No effect

Mu

Decrease

No effect

Mu, kappa

↓ transit

No effect

Kappa

Increase

No effect

Feeding

Mu, kappa, delta

↑ Feeding

↓ Feeding

Sedation

mu, kappa

Increase

No effect

Diuresis

Kappa

Increase

??

Prolactin

Mu

↑ release

↓ release

Mu and/or delta

↑ release

↓ release

Mu

Inhibit

??

Mu, delta

Inhibit

??

Respiratory GI Psychotomimesis

Growth hormone Acetylcholine Dopamine

Modified from Pasternak 1993

Opioids And Receptor Affinity Drug

Mu

Morphine

+++

Oxycodone

+++

Hydromorphone

+++

Hydrocodone

+++

Oxymorphone

+++

Methadone

Delta

Kappa

NMDA

NE

5HT

+++

---

+

+

Levorphanol

+++

---

Fentanyl

+++

Butorphanol

P

+++

Buprenorphine

P

--

Pentazocine

P

++

Nalbuphine

--

++

Tramadol

+

+

+++

Tapentadol

+

+++

+

+

-

Table adapted from Goodman and Gilman, 11th ed

The Opioids by Chemical Class Phenanthrenes

Benzomorphans

Phenylpiperidines

Diphenylheptanes

Central?

Morphine

Pentazocine

Meperidine

Methadone

Tramadol

Codeine Hydrocodone* Hydromorphone* Levorphanol* Oxycodone* Oxymorphone* Buprenorphine* Nalbuphine Butorphanol* Naloxone Heroin

Diphenoxylate Loperamide

Fentanyl Sufentanil Alfentanil Remifentanil

Propoxyphene

Tapentadol

* Indicates lack of 6-OH group, possibly decreasing risk of cross-tolerance of hypersensitivity Table adapted with permission from J. Fudin, PharmD www.paindr.com

Adverse Effects of Opioids CNS

Dependence, substance abuse, sedation, psychotomimetic, vertigo, myoclonus, resp. depression, neurocognitive

Gastrointestinal

Constipation, nausea, sphincter of Oddi pressure changes, LES / cardiac sphincter changes

Genito-urinary

Urinary retention

Integumentary

Flushing, urticaria, pruritus

Metabolic Cardiovascular

Stimulate ADH, prolactin, somatotropin, loss of libido Hypotension and reflex tachycardia

Hepatic

Rare

Renal

Rare

Ocular

Miosis

Immune

Decrease in immune function with chronic dosing Herndon. Exp Opin Pharm 2003.

Opioid Induced Hypogonadism  Hormones affected – Gonadotropin releasing hormone – Follicle Stimulating Hormone > Luteinizing hormone – Testosterone

 Symptoms – Loss of libido, impotence (men) – Infertility – Fatigue, depression, anxiety – Loss of muscle strength – Menstrual irregularities, galactorrhea (women) Katz N, et al. Clin J Pain 2009;25:170-175.

Opioid Induced Hyperalgesia  Toxicity of 3-position glucuronides (morphine and hydromorphone)  NMDA agonism?  Increased spinal endogenous activity  Numerous additional hypotheses  Increasing pain despite increasing doses of opioid  Often confused with tolerance

Pasero C, et al. J Perianesth Nurs 2012;27:46-50.

Renal Insufficiency Morphine

Accumulation of neurotoxic morphine-3-glucuronide, potential dose reduction

Codeine

Severe narcosis reported in chronic renal failure

Fentanyl

Potential increased T1/2, otherwise considered safe

Hydrocodone

Insufficient data, potential accumulation of glucuronide end – metabolites

Hydromorphone

Moderate impairment, reduce dose and titrate; Severe, switch agents

Levorphanol

Renally excreted metabolite accumulates. Avoid use or use caution

Meperidine

Avoid

Methadone

No known risks – potential shift in elimination from renal to fecal

Oxycodone

Increased AUC; dose conservatively

Oxymorphone

Insufficient data

Tramadol

CrCl < 30ml/min decrease dose to BID

Buprenorphine

Insufficient data, inactive metabolites

Butorphanol

½ recommended doses

Nalbuphine

No changes necessary Compiled from www.lexicomp.com. Accessed June 17 2012.

Hepatic Insufficiency Morphine

Reduce dose and interval

Codeine

Insufficient data; theoretical decrease in analgesia

Fentanyl

High extraction drug; decrease dose with decreased hepatic blood flow

Hydrocodone Hydromorphone

Use caution with concurrent acetaminophen dosing, theoretical accumulation Insufficient data, dosing adjustment should be considered

Levorphanol

Use with caution, considered reduced initial dose

Meperidine

Avoid

Methadone

Avoid in severe liver disease

Oxycodone

Increased AUC; dose conservatively, decrease CR by 1/3 to ½

Oxymorphone Tramadol Buprenorphine

Contraindicated in mod-sev hepatic impairment. Low dose in mild Cirrhosis: 50mg q12 max; variable for CR formulations Caution due to extensive hepatic metabolism; Patch: 5mcg/hr

Butorphanol

½ recommended doses, Q6 dosing; Nasal, 1mg w/ 2nd dose 90-120 minutes later

Nalbuphine

Caution and reduce dose Compiled from www.lexicomp.com. Accessed June 17 2012.

Pregnancy / Lactation Opioid

Pregnancy Cat.

Breast milk

Morphine

C

Compatible, enters milk

Codeine

C

Compatible, enters milk*

Hydrocodone

C

Not recommended, enters milk

Hydromorphone

C

Not recommended, enters milk

Levorphanol

C

Safety unknown

Oxycodone

B (not CR)

Not recommended, enters milk

Oxymorphone

C

Use caution, enters milk

Buprenorphine

C

Not recommended, enters milk

Nalbuphine

C

Not recommended, enters milk

Butorphanol

C

AAP compatible, enters milk

Naloxone

B

Safety unknown

Meperidine

C

Safety unknown

Fentanyl

C

Not recommended although AAP rates as compatible

Methadone

C

Not recommended although AAP rates as compatible * FDA has warned against use of codeine in breast feeding mothers

Use Of Opioids In Pediatrics Morphine

0.15 to 0.3mg/kg every 3 to 4 hrs (oral); 0.05 to 0.1mg/kg (IV)

Codeine

Not recommended for analgesia

Fentanyl

Not recommended for OPIOID NAÏVE in analgesia (conscious sedation)

Hydrocodone Hydromorphone

0.135mg/kg/dose every 4 to 6 hours of hydrocodone; 10-15 mg/kg/dose APAP (watch APAP intake) 0.03-0.08 mg/kg/dose every 3 to 4 hours (oral); 0.015 mg/kg/dose every 3 to 4 hours (IV)

Levorphanol

Insufficient data

Methadone

0.1-0.2mg/kg every 4 to 8 hours, then every 8 to 12 hours (oral); 0.1mg/kg every 4 to 8 hours for 3 doses, then every 6 to 12 hours (IV)

Oxycodone

> 6 yrs = 1.25mg every 4 to 6 hours as needed

Oxymorphone Tramadol Buprenorphine

Insufficient data No data in children: fixed dosages in US > 2 yrs = 2 – 6 mcg/kg every 4 to 6 hours (slow IV or IM; opioid naïve)

Butorphanol

No dosing recommendations available

Nalbuphine

> 1 yr = 0.1 – 0.2 mg/kg every 3 to 4 hours (do not exceed 20mg/dose or 160mg / day)

Use Of Opioids In Geriatrics  Older patients have higher sensitivity to opioids  More profound hemodynamic effects  Generally have decreased opioid need  Calculate creatinine clearance and factor this into equianalgesic conversions

Fate of Select Opiates and Opioids Tramadol

Oxycodone CYP 2D6

oxymorphone

& 3A4

noroxycodone

CYP 2D6

Fentanyl CYP 3A4

fentanyl

norfentanyl

M1

Hydrocodone CYP 2D6

Buprenorphine

Codeine

hydromorphone

inactive

CYP 3A4

CYP 2D6

norbuprenorphine

morphine

H3G

H6G Meperidine

M3G

M6G

normeperidine

meperidinic acid

Morphine  Gold standard opioid  All equianalgesic tables based upon comparison with morphine  Undergoes glucuronidation

– Morphine-3-glucuronide (neurotoxicity and potentially hyperalgesia) – Morphine-6-glucuronide (analgesia, accounts for ~ 1% of metabolic product)

 3:1 oral to parenteral potency ratio  T1/2 of 2 to 4 hours  Onset of action 30 min (oral) 5 min (I.V.)  Duration of action 4 hours

Codeine  Low potency analgesic  Great for antitussive  Must be converted to morphine by CYP 2D6  One of the most constipating opioids  Approximate equal analgesia = 1/30 as potent

M3G

Codeine

CYP 2D6

morphine

M6G Prommer E. J Opioid Manag 2011;7:401-406.

Hydrocodone Parent and metabolite active Hydrocodone to hydromorphone by CYP 2D6 Little effect of metabolite on analgesia Mostly highly prescribed med in U.S. Approximate equal analgesia = ½ to 1x as potent as morphine Will S 3187 pass (hydrocodone as a C-II) Kaplan. J Pharmacol Exp Ther 1997.

Hydromorphone Glucuronidated to similar metabolites as morphine (H-3G and H-6-G) 4:1 oral to parenteral potency ratio T1/2 of 2 to 4 hours Onset of action 30 min (oral) 5 min (I.V.) Duration of action 4 hours Approximate equal analgesia = 5x as potent

Oxycodone Active parent drug Metabolized to oxymorphone via CYP 2D6 CYP enzyme inhibition or induction little effect on analgesia but may predispose to toxicity Approximate equal analgesia = 2x as potent T1/2 of 2 to 3 hours CR reformulated

Oxymorphone  Active metabolite of oxycodone  Undergoes glucuronidation and reduction  Onset and duration similar to others  T1/2 of ~ 7 hours  Opana and Opana ER (PO)  Numorphan (IV)  10:1 oral to parenteral potency ratio  Approximate equal analgesia = 3 to 4x as potent as morphine

Tramadol  O-demethylated to active metabolite (M1)  Weak mu-opioid agonist  Weak NE/5HT reuptake inhibition  Caution for seizures and serotonin syndrome  400mg / day max dose (IR) and 300mg / day (ER)

Tramadol

CYP 2D6

M1

Slanar O, et al. Bratis Lek Listy 2012;113:152-155. (Abstract)

Nalbuphine Metabolized to inactive metabolites hepatically Stimulates Kappa, antagonizes Mu receptors (use caution in opioid tolerant) Equianalgesic to morphine, more dysphoria Available only parenterally Used frequently in labor / delivery and may decrease active first stage of labor Kim TH, et al. J Obstet Gynaecol 2011;31:724-727.

Butorphanol  Metabolized primarily to hydroxybutorphanol (inactive) hepatically  Kappa agonist, Sigma agonist, Mu antagonist and partial agonist  Available as nasal spray and parenteral (in US)  Equianalgesic dose of 1:8 (don’t convert in opioid tolerant individuals)  Used commonly in refractory migraine (AHS)  Used commonly in labor / delivery (hindered by sedation) Wu Z, et al. J Anesth 2012 (In Press).

Maity A, et al. Perspect Clin Res 2012;3:16-21.

Pentazocine High history of abuse (Ts and Blues) Mixed agonist / antagonist –Agonist at Kappa –Antagonist and partial agonist at Mu

Rarely used in clinical practice today –Query of IL PMP database revealed no prescriptions dispensed in past 12 months

Meperidine  Largely phased out as analgesic – Ceiling dose due to toxic metabolite (normeperidine) – Accumulation in renal insufficiency

 Still used in – acute pancreatitis (rarely) – post-anesthesia rigors (commonly)

 Duration of analgesia 2 to 3 hours  Approximate equal analgesia = 1/10x as potent  Oral meperidine of little analgesic use

Fentanyl  Metabolized via CYP 3A4 to inactive metabolites  T1/2 of ~ 3 hours intravenous  Onset of analgesia – IV is almost instantaneous – Transdermal 12-24 hours – Transmucosal 5 to 15 minutes

 Duration of analgesia – IV duration ~ 30 to 60 minutes – Transdermal not applicable (although consider depot effect of 12 hrs)

Duragesic [package insert]. Vacaville, CA: Janssen Pharmaceuticals, Inc., October 2011.

http://www.drugs-forum.com/forum/showthread.php?t=13456. Accessed June 15, 2012.

http://www.drugs-forum.com/forum/showthread.php?t=13456. Accessed June 15, 2012.

http://www.drugs-forum.com/forum/showthread.php?t=13456. Accessed June 15, 2012.

“Patching” together dosing for fentanyl TTS

The “2:1 trick” Oral ME daily fentanyl TTS mcg / hr

Duragesic [package insert]. Vacaville, CA: Janssen Pharmaceuticals, Inc., October 2011.

Donner B, et al. Pain 1996;64:527-534.

Breitbart W, et al. Oncology 2000;14:695-705.

Transmucosal Fentanyl  Oral Transmucosal Fentanyl Citrate (Actiq, generics)  Fentora  Onsolis 0.45

Cmax

 Abstral

Based on 200mcg doses 70

0.4

60

0.35 0.3

Tmax

50 Actiq

Actiq

0.25

Fentora 40

Fentora

0.2

Onsolis 30 Abstral 20

Onsolis

0.15 0.1 0.05 0

10 0

Abstral

Intranasal Fentanyl (Lazanda)  Simple and easy to prime (red line to green)  Must be used within 5 days of last use OR  Must be used within 14 days of priming  Special “pouch” to prime into  2 hr delay between doses  Start with 100mcg spray  Assess relief after 30 min

Sublingual Fentanyl (Subsys)

TIRF REMS

Take Home On Fentanyl Do not convert mcg to mcg –OTFC and Fentora have specific directions

Cmax, Tmax, and bioavailability are NOT linear Dosing should follow prescribing information Ensure appropriate disposal

Buprenorphine  Partial mu-opioid agonist, kappa antagonist, and nociceptin active  Comparatively high binding affinity for mu-receptor  Transdermal patch

– 7 day matrix patch (drug embedded in adhesive) – Available in 5mcg/hr, 10mcg/hr, and 20mcg/hr – Doses above 20mcg/hr not recommended due to QTc prolongation – Difficult to reverse in overdose or acute pain (Patch should be removed 4872 hrs prior to surgery)

 Sublingually

– With or without naloxone Butrans [package insert]. Stamford, CT: Purdue Pharma, 2010.

Brown SM, et al. Anesthesiology 2011;115:1251-1260.

Buprenorphine Patch Dosing Daily morphine equivalents

Starting dose of buprenorphine patch

< 30mg / 24 hours

5 mcg/hr buprenorphine patch

30-80mg / 24 hours

10 mcg/hr buprenorphine patch

Morphine equivalents > 80mg / 24 hours may not be suitable candidates Patients should be weaned to < 30mg morphine equiv. / 24 hours for 7 days Dose titration may occur every 72 hours

Butrans [package insert]. Stamford, CT: Purdue Pharma, 2010.

Hold The Naloxone Or Supersize?  Buprenorphine / naloxone for pain mgmt  Tablet and film  Pros

– Potentially less risk of misuse in those with polysubstance abuse – MAYBE less constipation but no data to support – Less euphoria

 Cons

– Acute pain treatment difficult

 Is there a therapeutic advantage?

– Not apparently

Ling W, et al. J Addict Med 2012;6:118-123.

Methadone  Active parent  Metabolism via N-demethylation – CYP 3A4, 2B6, 2C19 – Inactive metabolites

 Mu, kappa, delta opioid activity, NE/5HT reuptake, NMDA antagonism  T1/2 of 7 to 59 hours  May cause QTc prolongation

 Specific monitoring recommendations – EKG at baseline, 30 days, and annually

– Additional screening in doses > 100mg daily or syncope / seizures – QTc 450 – 500 ms: discuss risks, EKG more frequently

– QTc > 500 ms: consider discontinuation or dose reduction  Remember potassium monitoring and other drugs!

Krantz MJ, et al. QTc interval screening in methadone treatment. Ann Intern Med 2009:150:387-395.

Methadone (cont’d) 1. Changes in equianalgesic potency based on previous morphine equivalents 2. Avoid dose adjustments sooner than 5-7 days 3. Reduce dose by 50-75% following conversion 4. Numerous methods for converting 5. “Stop and go” vs cross-titration 6. Start low in opioid naïve (2.5mg Q12)

Toombs. Am Fam Physician 2005.

Methadone Conversion Techniques  Bruera et al. Cancer 1996;78:852-857.  Tse DM, et al. Palliat Med 2003;17:206-211.  Nauck F, et al. Am J Hosp Palliat Care 2001;18:200-202  Ripamonti C, et al. J Clin Oncol 1998;16:3216-3221.  Morley JS, Makin MK. Pain Rev 1998;5:51-58.  Ayonrinde OT, et al. Med J Aust 2000;173:536-540.  Friedman LL, et al. Clin Fam Prac 2004;371-393.

(Modified Morley-Makin)  Dolophine prescribing insert McPherson ML. Demystifying opioid conversion calculations. Bethesda, MD: American Society for Health-System Pharmacists, Inc; 2010.

Levorphanol  Limited availability  Opioid + NMDA activity  T1/2 of 12 to 16 hours  Duration of action 4 to 8 hours

McNulty. J Pall Med 2007.

Tapentadol (Nucynta and Nucynta ER)  Weak mu-opioid agonist, CII with abuse liability  Weak NE reuptake inhibitor, watch SNRIs  Immediate release (50mg, 75mg, 100mg) – Max dose 700mg day 1, 600mg daily thereafter

 Extended release (50mg, 100mg, 150mg, 200mg, 250mg) – Max dose 500mg daily

Daniels SE, et al. Current Medical Research and Opinion 2009;25:765-776.

Tapentadol ER (Nucynta速 ER) In OA Of The Knee LSM WOMAC Score at 12 weeks

0

WOMAC Pain

WOMAC Function

WOMAC Stiffness n = 1023

-0.2

-0.4

Tapentadol ER

-0.6

Oxycodone CR Placebo

-0.8

-1

-1.2

p < 0.001

p = 0.006

p = 0.053

-1.4

Afilalo M, et al. Clin Drug Invest. 2010.

Commercially Available Oral Opioids in US (soln and susp excluded) Combination

Immed. Release

“Long acting”

Hydrocodone / APAP:

Morphine

Morphine-LA

2.5/500; 5/325; 5/500; 7.5/325; 7.5/500; 7.5/650; 7.5/750; 10/325;10/500; 10/650; 10/660; 10/750

10; 15; 30

Tramadol: 50mg Tapentadol: 50, 75, 100mg

15; 30; 60; 100; 200; Kadian specific: 10; 20; 50; 80 Avinza specific: 90; 120 Embeda specific: 20;30;50;60;80; 100

Hydrocodone / Ibuprofen:

Oxycodone

Oxycodone-LA

5/200; 7.5/200

5; 15; 30

10; 20; 40; 80

Oxycodone / APAP:

Hydromorphone

Oxymorphone-LA

2.5/325; 5/325; 7.5/325; 10/325; 5/500; 7.5/500; 10/650

2; 4; 8

5; 7.5; 10; 15; 20; 30; 40

Oxycodone / Ibuprofen:

Oxymorphone

Fentanyl-TTS

5/400

5; 10

12.5; 25; 50; 75; 100 (mcg/hour)

Codeine / APAP:

Codeine

Methadone

15/300; 30/300; 60/300

15; 30; 60

5; 10 (40mg restricted use in US)

Propoxyphene / APAP:

Fentanyl (buccal / OTFC)

Levorphanol

50/325; 65/650; 100/325; 100/500; 100/650

0.1; 0.2; 0.4; 0.6; 0.8; 1.2; 1.6

2

Equianalgesic Opioid Dosing Drug

IV (mg)

Oral (mg)

Morphine

10

30

Buprenorphine

0.3

0.4 (SL)

Codeine

100

200

Fentanyl

0.1

--

Hydrocodone

--

30

Hydromorphone

1.5

7.5

Meperidine

100

300

Oxycodone

10

20

Oxymorphone

1

10

McPherson ML. Demystifying opioid conversion calculations. Bethesda, MD: American Society for Health-System Pharmacists, Inc; 2010.

Adjusting Doses  Incomplete cross-tolerance – When switching from one opioid to another, we reduce the dose of the new opioid by 25-50% – Exceptions • Converting to transdermal fentanyl (TDF) • Converting to methadone

McPherson ML. Demystifying opioid conversion calculations. Bethesda, MD: American Society for Health-System Pharmacists, Inc; 2010.

Adjusting Doses (cont’d)  Increasing doses – Moderate-severe: ↑ total daily dose by 50-100% – Mild-moderate: ↑ total daily dose by 25-50% – Short-acting agents (IR, single agent): Q 2-4hrs – Long-acting agents (ER): Q 24 hrs

McPherson ML. Demystifying opioid conversion calculations. Bethesda, MD: American Society for Health-System Pharmacists, Inc; 2010.

Topical NSAIDs Diclofenac epolamine 1.4% patch (Flector®) Diclofenac sodium 1% gel (Voltaren®) Diclofenac sodium 1.5% soln (Pennsaid®)

Diclofenac Epolamine Topical Patch (Flector®)  10cm X 14cm matrix patch  Indicated for acute pain due to minor sprains, strains, and contusions  Twice daily application – Application to affected site – Avoid damaged or non-intact skin

 Removal required – Bathing / showering – MRI Flector [package insert]. Bristol, TN: King Pharmaceuticals; 2009.

® Diclofenac 1% Gel (Voltaren Gel)

 Indicated for the relief of the pain of OA of joints amenable to topic treatment  Dosing – do not exceed 32 grams each 24hrs – Lower extremities – 2 grams QID – Upper extremities – 4 grams QID

 Avoid exposing application site to: – Sunlight or similar – Direct heat – Sunscreens, moisturizers, insect repellants, etc.

Voltaren Gel [package insert]. Chadds Ford, PA: Endo Pharmaceuticals; 2009.

Change in WOMAC Score at 12 weeks

Diclofenac Gel (Voltaren速 Gel) In OA Of The Knee 0

WOMAC Pain

WOMAC Function

Pain on Movement Diclofenac Placebo

-5

-10

-15

n = 492

-20

-25

-30

p = 0.01

p = .001

p < 0.002 Barthel HR, et al. Semin Arthritis Rheum. 2009.

Diclofenac Sodium Topical Solution 1.5% (Pennsaid®)  Indicated for the treatment of signs and symptoms of osteoarthritis of the knee  Dosing – 40 drops to affected knee QID – Dispense only 10 drops at once

 Avoid showering / bathing for 30 minutes  Avoid exposing application site to: – Sunlight or similar – External heat or occlusive dressings Pennsaid [package insert]. St. Louis, MO: Covidien; 2010.

Change in WOMAC Score at 12 weeks

Diclofenac / DMSO (Pennsaid速) Solution In OA Of The Knee WOMAC Pain

WOMAC Function

WOMAC Stiffness

0 -2 -4 -6 -8

p = 0.112 p = 0.035

p = 0.015 p = 0.009

O-Diclo

-10

DSMO

-12

Placebo

-14 -16 -18

T-Diclo

n =775 p = 0.034 p = 0.026

-20

T-Diclo: topical diclofenac; O-Diclo: oral diclofenac; DMSO: dimethyl sulfoxide Simon LS, et al. Pain. 2009.

Comparative Cmax Of Diclofenac Formulation

Cmax (ng/mL)

Diclofenac 50mg tablet

1298

Diclofenac 75mg tablet

2367

Diclofenac epolamine patch (Flector速)

8.8

Diclofenac gel 1% (Voltaren速 Gel)

53.8

Diclofenac gel 3% (Solaraze速) Diclofenac / DMSO soln. (Pennsaid速)

4 19.4 Arthrotec [package insert]. New York, NY: Pfizer; 2010.

Flector [package insert]. Bristol, TN: King Pharmaceuticals; 2009.

Voltaren Gel [package insert]. Chadds Ford, PA: Endo Pharmaceuticals; 2009.

Solaraze [package insert]. Melville, NY: PharmaDerm; 2008.

Pennsaid [package insert]. St. Louis, MO: Covidien; 2010.

Diclofenac Adverse Effects  Cardiovascular risk: boxed warning – Perioperative use in CABG contraindicated – May cause increased risk of MI and stroke, which can be fatal – Risk may be greater with longer duration and pre-existing CV disease

 Gastrointestinal risk: boxed warning – Increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation.

– Events may occur at any time during use and be asymptomatic

 Elevated liver transaminases

Adverse Effects AE

Topical (n=154) %

Placebo (n=157) %

Vehicle (n=161) %

Oral (n=151) %

Topical + Oral (n=152) %

Any

62.3

57.3

60.2

62.3

64.5

Abdominal Pain

3.2

0.6

3.1

7.3

2.0

Dyspepsia

2.6

3.8

3.7

4.0

3.3

Nausea

0

0

0.6

2.0

3.3

LFT abnormality

1.9

0.6

3.7

7.9

7.2

Digestive System

Simon LS, et al. Pain. 2009.

Antman EM, et al. Circulation. 2007.

Which NSAIDs are safe?

Antman EM, et al. Circulation. 2007.

Which NSAIDs are safe? (contâ&#x20AC;&#x2122;d)

Trelle S, et al. British Medical Journal. 2011.

Which NSAIDs are safe? (contâ&#x20AC;&#x2122;d)

Trelle S, et al. British Medical Journal. 2011.

Which NSAIDs are safe? (contâ&#x20AC;&#x2122;d)

Trelle S, et al. British Medical Journal. 2011.

Which NSAIDs are safe? (contâ&#x20AC;&#x2122;d)

Trelle S, et al. British Medical Journal. 2011.

® Capsaicin 8% (Qutenza )  Indicated for post-herpetic neuralgia  Multiple step instructions – 1. Delineate site of hyperalgesia – 2. Trace site with overlay paper – 3. Cut patch to match area of hyperalgesia – 4. Apply topical local anesthetic to application site – 5. Apply for 1 hour (up to 4 patches concurrently may be used) – 6. Remove patch and clean site with proprietary cleanser

 May repeat > 3 months  Should be performed in medically supervised setting Qutenza [package insert]. New York, NY: Pfizer; 2010.

Capsaicin 8% in PHN  Double-blind, parallel group trial  N = 402, duration 12 weeks  Capsaicin 8% patch vs. capsaicin 0.04% patch  Pretreatment with lidocaine, post treatment with oxycodone 0

-5 -10

8%

-20

0.04%

% Change in NPRS -15

P = 0.001

NPRS = Neuropathic Pain Rating Scale

-25

-30

-35

Backonja M. et al. NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: A randomised, double-blind study. Lancet Neurol 2008;7:1106.

Lidocaine  Topical anesthetic and Class 1b anti-arrhythmic  Sodium channel blockade Na(v) 1.7  Inhibition of Acid Sensing Ion Channels (ASIC)  Available via OTC (0.5-4%) and prescription (5%)

– OTC: Anestafoam®, Solarcaine®, LMX®, Anecream®, Lidamantle®, Topicaine®, Burn Jel®, Regenecare®, Unburn®, Band-Aid® – Rx: Lidoderm®, Hurricaine®, Xylocaine®

 Lidocaine 5% patch applied directly to area of PHN  No more than 3 patches concurrently  12 hours on, 12 hours off

Lin J, et al. Inhibition of acid sensing ion channel currents by lidocaine in cultured mouse corticol neurons. Anesth Analg 2011:112:977-81.

Kaliq W, et al. Topical lidocaine for the treatment of postherpetic neuralgia. Cochrane Database Syst Rev 2007;18:CD004846.

So Which Anticonvulsant? Non-obese, co-morbid anxiety –Gabapentin, pregabalin

Obese, or co-morbid seizure disorder –Lacosamide?, zonisamide, topiramate, levetiracetam

Co-morbid bipolar disorder or sz disorder –Oxcarbazepine, lamotrigine, carbamazepine, valproic acid TIMI Bipolar Guidelines Hearn L, Derry S, Moore RA. Lacosamide for neuropathic pain and fibromyalgia in adults.

Cochrane Database of Systematic Reviews 2012, Issue 2. Art. No.: CD009318. DOI: 10.1002/14651858.CD009318.pub2.

So Which Antidepressant?  TCAs (NE > 5HT) – amitriptyline – imipramine – desipramine (20 amine) – nortriptyline (20 amine)

 SSRIs (5HT > NE) – paroxetine – citalopram – escitalopram

 SNRIs – venlafaxine – desvenlafaxine – duloxetine – milnacipran (3:1 NE)

 Atypicals – bupropion – mirtazapine – trazodone – vilazodone?

® Duloxetine (Cymbalta )  Serotonin / Norepinephrine Reuptake Inhibitor (plus dopamine)  Indications – – – – –

Major Depressive Disorder (MDD) Generalized Anxiety Disorder (GAD) Diabetic Peripheral Neuropathic Pain (DPNP) Fibromyalgia (FMS) Chronic Musculoskeletal Pain (OA and LBP)

 Dosing

– 30 to 120mg for MDD and GAD – 30 to 60mg for DPNP, FMS, OA, and CLBP

     

Boxed Warning – suicidality Drug interactions with CYP 1A2 and 2D6 No direction on monitoring serum transaminases Overall Number Needed to Treat (NNT) vs. Number Needed to Harm (NNH) (13 weeks) NNT = 1:5-8 NNH = 1:8-12

Adverse Effects of Duloxetine  Adverse effects > 5% – Nausea, dry mouth, insomnia, sleepiness, constipation, dizziness fatigue

 Adverse effects < 1% – Hepatoxicity, allergic/hypersensitivity reactions, pneumonia, suicidality

 Start with 30 mg po qd for a week (due to nausea); do not exceed 60 mg po qd

® Milnacipran (Savella )

 SNRI with 3:1 NE to 5HT reuptake activity  FDA approved for fibromyalgia  Dosing – 12.5mg QD X 1 day – 12.5mg Q12 X 2 days – 25mg Q12 X 4 days – 50mg Q12 thereafter (doses > 200mg show no addition benefit)

 Still requires monitoring for mood changes!  Baseline SCr recommended

Skeletal Muscle Relaxants  Cyclobenzaprine – sedation, structurally a TCA  Tizanidine – sedating, hypotension, best data  Methocarbamol – less sedating, limiting evidence  Orphenadrine – sedating, sodium channel blockade  Carisoprodol – sedating, high abuse potential  Diazepam – sedating, high abuse potential  Metaxalone – less sedating, expensive  Baclofen – data primarily intrathecal  Dantrolene – hepatotoxicity

Chronic Pain Syndromes

Prevalence, US pop.

 Chronic low back pain ± radiculopathy (CLBP)  Osteoarthritis (OA)  Painful Diabetic Neuropathy (PDN)  Fibromyalgia syndrome (FMS)  Rheumatoid arthritis (RA)

National Center for Health Statistics; Health, United States, 2007.

With Chartbook on Trends in the Health of Americans; Hyattsville, MD: 2007

Low Back Pain Practice Guidelines  Focused history to subclassify low back pain – Nonspecific low back pain – Back pain assoc. w/ radiculopathy or spinal stenosis – Back pain assoc. with other spinal cause

 Imaging

– None – nonspecific low back pain (strong rec) – MRI – progressive neurologic deficits (strong rec) – CT – candidate for surgery or epidural steroid injection (strong rec)

 Education

– Expected course, advise to remain active, self-care options

 Treatment

– 1st line APAP or NSAIDs + self care options (strong rec) – Spinal manipulation, intensive interdisciplinary rehab, exercise, yoga, CBT, progressive relaxation (weak rec) Chou R, et al. Diagnosis and treatment of low back pain: A joint clinical practice guideline from the American College of Physicians and the American Pain Society. Ann Intern Med 2007;147:478-491.

Osteoarthritis Practice Guidelines Joint protection APAP 1st line NSAIDs 2nd line Non-Pharm (TENS, PT, OT, hot/cold therapy) 3rd line Opioids when all else fails (where does tramadol fit in)?

Hochberg MC, et al. ACR 2012 Recommendations for the use of nonpharmcologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res 2012;64:465-474.

Noninflammatory OA

Inflammatory OA*

NonPharm

NonPharm

Acetaminophen

NSAIDs (PRN then scheduled)

NSAID trial

IA corticosteroids

IA Corticosteroids

Colchicine

Trial of adjuvant therapies, topic therapies, IA hyaluronidase, lower potency opioids

Surgery, including joint replacement, opioids, and chronic pain management

*Inflammatory arthritis is evidenced by history of swelling, night pain, morning stiffness greater than 30 minutes; active synovitis on physical examination; chondrocalcinosis on radiographs; rhomboid, positively-birefringent crystals from arthrocentesis; or visualization of crystalline material upon arthroscopy

Note: Not guideline-based Kalunian KC. Pharmacologic therapy of osteoarthritis. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2012.

Guideline Driven Treatment Diabetic Peripheral Neuropathy Intervention

Level A Recommendation

Antidepressants

Anticonvulsants

American Academy of Neurology American Academy of Neuromuscular and Electrodiagnostic Medicine American Academy of Physical Medicine and Rehabilitation European Federation of Neurological Societies

Level B Recommendation

Not Recommended

Venlafaxine Duloxetine Amitriptyline Pregabalin

Gabapentin Sodium Valproate

Oxcarbazepine Lamotrigine Lacosamide

Opioids

Tramadol Oxycodone Morphine

Other

Dextromethorphan Capsaicin Isosorbide Dinitrate

Clonidine Pentoxifylline Mexiletine

Transcutaneous Electrical Nerve Stimulation (TENS)

Magnetic therapy Reiki therapy Laser therapy

Non-Pharm

Bril V, et al. Neurology 2011;76:1758-1765.

Attal N, et al. European Journal of Neurology 2010;17:1113-1123.

Fibromyalgia Recommendations  Address and treat sleep hygiene  Pharmacotherapy – TCAs – [pregabalin, duloxetine, and milnacipran approved since publication]

 Cardiovascular exercise  Cognitive behavioral therapy  Intense patient education

Goldenberg DL, et al. Management of fibromyalgia syndrome. JAMA 2004;292:2388-95.

Fibromyalgia Impact Questionnaire Rating Parameters Likert (Always, Most, Occasionally, Never, N/A

Continuous data (in days over past week)

Visual Analog Scale (over past 7 days)

Functionality and Symptoms Shopping, laundry, cook, dishes, vacuum, make beds, walk several blocks, visit with friends / relatives, yard work, drive, stairs 1.

2.

How many days did you feel good?

How many days did you miss work, including housework, due to FMS? No problem with work

Great difficulty with work

No Pain

Very severe pain

No tiredness

Very tired

Awoke well rested

Awoke very tired

No stiffness

Very stiff

Not anxious

Very anxious

Not depressed

Very depressed Burckhardt, C.S., et al. J Rheumatol 1991;18:728-733.

Treatment Guidelines (EULAR) Recommendation

Strength of Recommendation

Level of Evidence

Antidepressants

A

1b

Tropisetron, pramipexole, and pregabalin

A

1b

Tramadol

A

1b

Heated pool treatment

B

2a

Individual exercise programs (aerobic or weights)

C

2b

Relaxation, rehabilitation, physiotherapy, counseling

C

2b

Cognitive behavioral therapy

D

4

Comprehensive assessment of pain and functioning

D

4

Multidisciplinary approach using non-pharm and pharm interventions

D

4

Acetaminophen and weak opioids

D

4

Carville SF, et al. Ann Rheum Dis 2008;67:536-541.

Symptom-Specific Interventions Fatigue • PGB • MLN PGB – pregabalin

Sleep

Depressed

• PGB • DLX MLN – milnacipran

• DLX • MLN DLX - duloxetine

Hauser W, et al. J Pain 2010;11:505-521.

Complex Regional Pain Syndrome  Most common sympathetically maintained pain  Classified as Type 1 or Type 2

– Type 1 no discernable nerve lesion (previously RSD) – Type 2 definable nerve lesion (previously causalgia)

 Pathophysiology

– Neurogenic inflammation – CNS plasticity – Genetic predisposition

 Diagnosis

– Pain, swelling, decr. ROM, vasomotor and skin changes, and patchy bone demineralization – Autonomic testing (resting sweat output, resting skin temp, QSART) – Imaging (plain film radiography, scintography, CT, MRI) Stanton-Hicks MD, Burton AW, Bruehl SP, et al. An updated interdisciplinary clinical pathway for CRPS: report of an expert panel. Pain Pract 2002; 2:1.

Complex Regional Pain Syndrome (cont’d)  Prevention – Early mobilization! (post-MI, post-stroke) – Ascorbic acid following fracture

 Treatment (may be Stage I-III specific) – PT / OT – less pain but no sig. difference in ROM – Pharmacotherapy • TCAs, anticonvulsants, NSAID +/- opioid (Stanton-Hicks) • Bisphosphonates, clonidine (IV and transdermal), capsaicin, glucocorticoids, α-blockers, IV ketamine

– Interventional

• Tender point injections, regional sympathetic blocks Petchkrua W, Weiss DJ, Patel RR. Reassessment of the incidence of complex regional pain syndrome type 1 following stroke. Neurorehabil Neural Repair 2000; 14:59.

Stanton-Hicks MD, Burton AW, Bruehl SP, et al. An updated interdisciplinary clinical pathway for CRPS: report of an expert panel. Pain Pract 2002; 2:1.

Central Post-Stroke Pain  Most common type of Central Pain (1:100-200 pts)  Unilateral pain and dysesthesia – Associated with sensory neuropathy – Not explained by a lesion of the trigeminal nerve – Develops within 6 months of documented stroke – Corresponding lesion visualized by CT or MRI

 Prevention – unknown  Treatment – TCAs first line (other NE or 5HT modulators reasonable) – Gabapentin / pregabalin second line (best data with lamotrigine) – Opioids third line Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004; 24 Suppl 1:9.

Post-Operative Pain  Pre-emptive analgesia

– NSAIDs, clonidine, gabapentin, pregabalin – Neuraxial (intrathecal or epidural) or regional block

 Post-operative pain control

– Minimize dose and maximize analgesia – Patient controlled epidural analgesia (opioid + anesthetic) – Patient controlled intravenous analgesia (opioid) – Ketorolac

 No PCA by proxy!  No basal rate in opioid naïve patients!  Watch for buprenorphine before surgery  Restart oral methadone as soon as possible

Werawatganon T, Charuluxanun S. Patient controlled intravenous opioid analgesia versus continuous epidural analgesia for pain after intra-abdominal surgery. Cochrane Database Syst Rev 2005; :CD004088.

STOP-BANG To Screen For OSA  Snore  Tired during the day  Obstruction at night (do you stop breathing?)  Pressure (high blood pressure or treated HTN)  BMI > 28  Age > 50  Neck circumference > 17 for a male > 16 female  Gender are you a male Porhomayon J, et al. Lung 2011;189:359-367.

Abrishami A, et al. Can J Anaesth 2010;57:423-438.

Etiologies of Cancer Pain  “Tumor” associated

– Malignancy may directly invade tissue and recruit inflammatory and nociceptive chemokines (Somatic) – Tumor may cause distension of hollow or encapsulated organ (Visceral) – Tumor may impinge directly upon nerves (Neuropathic) – Tumor or metastasis may directly infiltrate bone (Bone)

 Treatment associated

– Chemotherapeutic regimens result in neurotoxicity (Neuropathic) – Radiation therapy may result in tissue or nerve destruction (Somatic and Neuropathic) – Chemotherapeutic regimens or radiation result in mucosal tissue toxicity (Somatic – Mucositis) – Oncologic surgery may result in complicated post-op pain (Somatic or Neuropathic)

Ferrell B, et al. Managing pain from advanced cancer in the palliative care setting. Clin J Oncol Nursing 2008;12:575-581.

Pain Crisis Considered an oncologic emergency Treatment in ED with consideration for admission Patients should be first stratified as opioid naïve or opioid-tolerant Administration route should be selected Numerous strategies exist, the 2 most common referenced below http://www.nccn.org/professionals/physician_gls/pdf/pain.pdf Walsh D, et al. Strategies for pain management: Cleveland Clinic Foundation guidelines for opioid dosing for cancer pain.

Pain Crisis Treatment – Opioid Naïve Cleveland Clinic Method

Pain Relief 5 minute respite

1mg IV morphine in 1 minute intervals for 10 minutes

NCCN Method

Pain Relief 2-5mg IV morphine with assessment in 15 minutes

Adjust dose for response

7-10 / 10 pain score = increase dose 50-100% 4-6 / 10 pain score = repeat previous dose < 4 / 10 pain score = continue “as needed Repeat for 2-3 cycles, reassess etiology if needed

Pain Crisis Treatment: Current Opioid Therapy  Similar strategies between recommendations  Bolus and breakthrough doses a function of previous 24 hour morphine equivalents (ME) – IV dosing bolus 2x the hourly ME, followed by 1x every 15 minutes until response achieved – PO dosing 2x the previous breakthrough dose given every 30 minutes until response achieved

 Restructure chronic opioid therapy once goal achieved Walsh D, et al. Strategies for pain management: Cleveland Clinic Foundation guidelines for opioid dosing for cancer pain.

Chronic Pain in Cancer  Consider “baseline” pain and “breakthrough” pain  The tenants of cancer pain mgmt is: – By the mouth – By the clock – By the patient

 When possible, we try to control pain with oral, long acting opioids  Always provide adequate short acting (IR) opioids for breakthrough pain Swarm R, et al. Adult cancer pain. J Natl Compr Canc Netw 2010;8:1046-1086.

Incidence and Types of Breakthrough Pain Breakthrough pain (BTP) occurs as frequently as 70-90% of advanced cancer patients Numerous approaches to classification –Incident (due to a predictable or unpredictable trigger) –Spontaneous / Idiopathic (no predictable trigger) –End of dose failure (increase in pain as long acting opioid wears off) Haugen DF, et al. Assessment and classification of cancer breakthrough pain: A systematic review. Pain 2010;149:476-482.

Breakthrough Pain Over Medication Around-the-Clock Medication

Ideal Breakthrough Medication

Bone Pain  Perhaps the most difficult type of pain to treat in cancer  May be classified as osteolytic or osteoblastic  May result in the following complications – Fracture – Nerve impingement or spinal cord compression – Hypercalcemia – Periosteal stretch and recruitment of inflammatory mediators

 Numerous treatment approaches http://en.wikipedia.org/wiki/File:Prostate-mets-102.jpg

Bone Pain Treatment  NSAIDs  Corticosteroids  Bisphosphonates  Denosumab  Calcitonin  Radiotherapy  Opioids

Bisphosphonates and Denosumab  Assessed using Skeletal Related Events (SRE) & Pain

– Fracture – Loss of stability / integrity of bone – Spinal cord compression – Need for radiotherapy or surgery due to symptomatic mets – Hypercalcemia

 Bisphosphonates

– Zoledronic acid (Zometa®, Reclast®) – Pamidronate – Ibandronate (Boniva®)

 Denosumab (Prolia®)

Devitt B, et al. Use of ibandronate in the prevention of skeletal events in metastatic breast cancer. Ther Clin Risk Manag 2008;4:453-458.

Monitoring and Universal Precautions  The “4 As” of assessment

– Analgesia (what's your pain score) – Activity (can you cut the grass, do laundry, bath) – Adverse effects (can you poop and pee) – Aberrant behaviors (doctor shopping, dose adulteration, etc)

 Universal precautions – Drug screening • Urine • Blood • Saliva

– Pill count – Prescription monitoring programs – Risk tools and interview

Other New Or Pipeline Options For Chronic Musculoskeletal Pain  Naproxen / esomeprazole combination  Ibuprofen / famotidine combination  Transdermal ketoprofen  Numerous abuse deterrent opioid formulations – Combination with antagonists – Combination with niacin

 Naproxinod  CGRP inhibitors  BDNF inhibitors  Calcineurin agonists