Non-opioid pharmcologic approaches for the

injured worker. From mechanisms, to

formulations, and efficacy.

What and how they work.

Steven Stanos, DO

Medical Director, Swedish Pain Services

Swedish Medical Group

Swedish Medical Center

Seattle, WA

Disclosures

2

Consulting:

Collegium

Daiichi Sankyo

Endo

MyMatrixx

Pfizer

Scilex

Teva

Research:

Grunenthal

Overview

• Pathophysiology

• Peripheral and central sensitization

• Review

• Anticonvulsants

• Antidepressants

• Muscle relaxers

• Topicals

• Focus on mechanisms of action

’00-’07 Analgesic Costs = $17.8 billion

4

Total Annual Cost ($billions)

Analgesics/NSAIDs

Opioids

Adjuvants 12.3

1.9

3.6

Rasu RS, et al. J Managed Care Spec Pharm. 2014;20:921-928.

5

Pre-Test #1

The proposed mechanism of action of

orphenadrine is:

a. Antihistamine CNS depressant

b. alpha agonist

c. GABA agonist

d. None of the above, mechanism of action

is unknown

Pre-Test #2

FDA approved in the 1960s, this medication is

approved as an “adjuvant therapy to rest, physical

therapy, and other measures for the relief of

discomforts.”

a. Metaxalone

b. Tizanidine

c. Lioresal

d. None of the above, this FDA indication is

bogus

7

Key Questions: Comparative benefits and

harms of:

1. Different phamacological therapies for acute or

chronic nonradicular low back pain, radicular,

or spinal stenosis?

2. Nonpharmacologic therapies including

multidisciplinary rehabilitation, exercises,

modalities, devices, psychological therapies,

acupuncture, massage, yoga, magnets. Chou R, et al. Noninvasive Treatments for LBP. Comparative Effectiveness Review No. 169. AHRQ Publication

No. 16-EHC004-EE. Rockville, MD. AHRQ; February 2016.

1.

Pharmacotherapy for Acute LBP

Chou R, et al. Noninvasive Treatments for LBP. Comparative Effectiveness Review No. 169. AHRQ Publication

No. 16-EHC004-EE. Rockville, MD. AHRQ; February 2016.

Findings

• Acetaminophen no more effective than placebo for

acute low back pain

• Duloxetine is more effective than placebo for pain and

function in patients with chronic low back pain

• New evidence for pregabalin for radicular pain is

inconsistent to reliably estimate effects

• Tricyclic antidepressants not effective vs placebo for

pain relief or function

• More specific types of exercises are effective

• Similar conclusions of multidisciplinary rehabilitation

and psychological therapies

Chou R, et al. Noninvasive Treatments for LBP. Comparative Effectiveness Review No. 169. AHRQ Publication

No. 16-EHC004-EE. Rockville, MD. AHRQ; February 2016.

IASP

NEUROPATHIC PAIN:

“initiated or caused by a primary lesion or dysfunction in the nervous system”

“Nociceptive” vs. “Non-Nociceptive”

Caterina, Cur Op in Neurobiology (9), 1999.

Cutaneous Sensation

C-fiber

•Small diameter

•Slow conducting

•Unmyelinated

A-δ

•Medium diameter

•Fast conducting

•Lightly myelinated

•Polymodal

Millan, Progress in Neurobiology, 1999.

Primary Afferent C & Aβ Fibers

Sensation Mediated

Fibre

Class

Threshold

For

Activation

Principal

Transmitters

Receptors

Engaged Physiological Pathological

C High SP/NKA

CGRP

EAA

NK

CGRP

NMDA

AMPA

mGlu

Noxious (pain)

Highly noxious

(hyperalgesia)

Cold Allodynia

(pain)

Aβ Low EAA AMPA Innocuous

(no pain)

Mechanical

allodynia

Neuropathic Pain: A PARADOX

Cutting a telephone wire

Spontaneous

Paresthesias

Dysesthesias

Pain

Movement evoked pain

Tenderness with

denervation

Peculiar symptoms

Paroxysmal

Electric shock-like

Tingling

Shooting

Burning

Neuropathic Pain

MECHANISMS

•Ectopic activity in sensitized C-nociceptors

•Regenerating nerve sprouts

•Recruitment of silent nociceptors

•Spontaneous/evoked activity in DRGs

•Neuronal “hyperexitability”

Molecular Changes

•Sodium channel accumulation

•Glutamate receptor activity

•Reduction of GABA-ergic inhibition

•Penetration of calcium into cells

Jensen T. European J Pain 2002; (6) A.

SKIN

Peripheral Sensitization

Peripheral Nerve

Terminal

Pressure ?

Plasma Extravasation Vasodilation

Heat 5-HT3

PGE2

Bradykinin

VR1 5-HT3 EP B1/B2

IL1ß

Mast Cell

Macrophage

(PKC)

TNF-α IL-6 LIF

IL1-R TrkA H+

PKC

TTXr (SNS/SNS2)

Sub P

Gene Regulation

TTXr

TTXs

H+

P2X ASIC

Adapted from Woolf CJ, et al. Science. 2000;288:1765-1768.

Tissue Damage

ATP

NGF

H1

Histamine

Ca2+

PKA

Central Mechanisms/ Wind Up

Hansson PT, Fields HL, Hill RG, Marchettini P eds, Neuropathic Pain: Pathophysiology and Treatment, International Association for the

Study of Pain Press, Seattle, 2001

Beydoun A, Backonja. J Pain Symp Management 2003.

GABA Modulate receptor

(-)GABA transaminase

(-) reuptake

NSAIDs

Tricyclic

Antidepressants

Antiepileptics

Topical

Analgesics

Tricyclic Antidepressants

• Central blockade of monoamine uptake

• Enhancement of descending inhibition

• Adrenergic blockade on sprouts, NMDA antagonistic effects,

opioid modification, and sodium channel blockade

• Constant vs. Paroxysmal pain

• Nortriptyline = Amitriptyline

(McQuay, Pain, 1996)

Tricyclic Antidepressants: Adverse Effects

• Commonly reported AEs (generally anticholinergic):

• blurred vision

• cognitive changes

• constipation

• dry mouth

• orthostatic hypotension

• sedation

• sexual dysfunction

• tachycardia

• urinary retention

• Desipramine

• Nortriptyline

• Imipramine

• Doxepin

• Amitriptyline

Fewest

AEs

Most AEs

AEs = adverse effects.

Tricyclic Antidepressants: Positive Controlled Trials

Max et al. Max et al. Neurology.Neurology. 19871987;37:589;37:589--596596; Max et al. ; Max et al. N Engl J Med.N Engl J Med. 19921992;326:1250;326:1250--12561256; ; SindrupSindrup et al. et al. Br J Clin Br J Clin

PharmacolPharmacol.. 19901990;30:683;30:683--691691; Max et al. ; Max et al. Pain. Pain. 19911991;45:3;45:3--99; Watson et al. ; Watson et al. Neurology.Neurology. 19821982;32:671;32:671--673673; Max ; Max

et al. et al. Neurology.Neurology. 1988;1988;38:142738:1427--14321432; Graff; Graff--Radford et al. Radford et al. ClinClin J Pain. 2J Pain. 2000000;16:188;16:188--192192; ; KishoreKishore--Kumar et al. Kumar et al.

ClinClin PharmacolPharmacol Ther.Ther. 19901990;47:305;47:305--312312; Raja et al. ; Raja et al. Neurology.Neurology. 20022002;59:1015;59:1015--10211021..

Pain relief1226Desipramine (12.5-250, PBO)Kishore-Kumar

Raja

Graff-Radford

Max

Watson

PHN

Max

Sindrup

Max

Max

Painful DPN

Study

Nortriptyline (10-160, PBO)

Amitriptyline (12.5-200, PBO)

Amitriptyline (12.5-150, PBO)

Amitriptyline (12.5, PBO)

Desipramine (12.5-250, PBO)

Desipramine (50 or 200, PBO),

Clomipramine (50 or 75, PBO)

Desipramine (12.5-150, PBO),

Amitriptyline (12.5-150, PBO)

Amitriptyline (25-150, PBO)

Agent (mg/d)

76

49

58

24

20

26

108

29

N

24

8

12

8

12

6

14

12

Weeks

Pain intensity, relief;

cognitive function

Pain intensity

Pain relief

Pain relief

Pain relief

Neuropathy

symptoms

Pain relief

Pain relief

Primary End Point

FDA-Approved for Neuropathic Pain

• Carbamazepine • Trigeminal neuralgia

• Duloxetine • Peripheral diabetic neuropathy

• Gabapentin, gabapentin ER, gabapentin enacarbil • Postherpetic neuralgia

• Lidocaine Patch 5% • Postherpetic neuralgia

• Pregabalin • Peripheral diabetic neuropathy

• Postherpetic neuralgia

• Tapentadol ER • Diabetic peripheral neuropathy

Anticonvulsants MOA

Medication Action Side Effects Interaction

Gabapenitin

Pregabalin

Ca++ Channel

modifiers

Short term memory loss,

weight gain, confusion Opioids

Topirimate

Ca++, Na++ chan,

GABA-ar, CA in, free

radical scavenger

fatigue, wt loss, nrw angle

glaucoma, renal stones BCPs, First gen AEDs

Tiagabine GABA Reuptake

inhibitor

Dyspepsia, drowsiness,

confusion, seizure First gen AEDs

Lamotrigine Ca++, Na+ chan, Dec

NMDA Ca, GABA-ar

Dizzy, somn, nausea, ataxia,

Stevens Johnson

Anti TB drugs, First

gen AEDs,

oxcarbazepine

Oxcarbazepine Na+ chan, K+ efflux Hyponatremia, nausea, HA,

dizzy, hepatotoxicity BCPs, cyclosporine

Levetiracitam

Blocks inhibitors of

GABA-ar (Zinc, beta

carboline)

Somnolence, dizzy, agitation,

headache, aggression None

Physician's Desk Reference. Montvale, NJ: Thomson PDR; 2005

Topiramate (Topamax) 25, 100, 200mg

1. Modulation of voltage-gated Na channels

2. Potentiate GABA inhibition

3. Block Glutamate neurotransmission

4. Modulate Ca channels

5. Inhibition of carbonic anhydrase

side effect. perioral paresthesias

Side effects: diarrhea, anorexia, somnelance, asthenia, weight loss, confusion

6. Renal stones: 2-4 times greater risk

7. Oligohydrosis, metabolic acidosis warning

Doses range between 200-400 mg/day for various pain conditions (off-label)

Chong, Clin J Pain (19),2003.

Lamotrigine (Lamictal) 25, 100, 150, 200 mg

•Blocks voltage-sensitive sodium channels

• Inhibits pre-synaptic glutamate release

•Lack of drug interactions

•No serum monitoring

•Rash

Zonisamide: MOA

• Reduces repetitive neuronal firing via blockade of Na+

channels1

• Reduces voltage-dependent T-type Ca+2 channels2, facilitates

dopaminergic and serotonergic neurotransmission1

• Weakly inhibits carbonic anhydrase2

• Blocks K+ evoked glutamate release3

• Long half life: 63 – 69 hours

• Sulfonamide derivative

1Schauf. Brain Res. 1987;413:185-188. 2Suzuki, et al. Epilepsy Res. 1992;12:21-27.

• Atypical GABAergic & glycine effects

• (-) zinc & beta carbolines, enhancing chloride ion influx at

GABA-A receptor

• No hepatic metabolism, low protein binding

• Rapid dosage titration

• Case reports of rectal use (1000 BID)

Dunteman APS, 2004

Levetiracetam (Keppra)

Gabapentinoids

33

Gabapentin (Neurontin)

• FDA approved for postherpetic neuralgia (PHN)

• Mechanism of action: modulates α-2 delta receptor

• Decreases Calcium into the cell

• PHN1: 1800-3600 mg/day

• Dosing: 300 mg day 1, 300 mg BID day 2, 300 mg TID

• ? Rising abuse

• Gabapentin agents

– Gabapentin Encarbil2 (Horizant): 600 mg – 1200 mg/day

– Gabapentin ER (Gralice): 300 mg – 1800 mg

34 1. Backonja M, Glanzman L. Clin Ther 2003;25:81-104.

2. Backonja M, et al. Pain Medicine 2011; 12:1098-1108.

Gabapentin vs Epidural Steroid for Radicular

Leg Pain

Design: Multicenter, randomized comp. effectiveness trial

N= 145,

Methods: oral medication & sham, placebo & ESI

Results: At 1 month:

Epidural group > gabapentin for worst leg pain score and

successful outcome, and lower low back pain

both groups improved leg pain

– ESI (3.3 points, -2.2)

– Gabapentin (3.7 points, -1.7)

– Maintained at 3 months

35 Cohen S, et al. BMJ 2015;350:1-9,

Pregabalin (Lyrica)

• FDA approved: neuropathic pain associated with PHN

or DPN

• PHN: 150-600 mg/day

• DPN: 150-300 mg/day

• Schedule V drug

36

Pregabalin: Predictable Response Versus Gabapentin

High BioavailabilityHigh BioavailabilityHigh BioavailabilityLinear PK ProfileLinear PK ProfileLinear PK Profile

Pregabalin Gabapentin

All doses

90%

900 mg, 60%

1200 mg, 47%

2400 mg, 34%

3600 mg, 33%

1800 mg Recommended

dose

LyricaLyrica®® (pregabalin) Capsules CV [package(pregabalin) Capsules CV [package insert]. New York, NY: Pfizer Inc; 2005insert]. New York, NY: Pfizer Inc; 2005; Neurontin; Neurontin®® (gabapentin) (gabapentin)

[package insert]. New York, NY: Pfizer Inc; 2004; [package insert]. New York, NY: Pfizer Inc; 2004; WescheWesche, , BockbraderBockbrader. . Presented at: 24th Annual Scientific Presented at: 24th Annual Scientific

Meeting of the American Pain Society; 2005.Meeting of the American Pain Society; 2005.

Dose (mg/d)Dose (mg/d)

0 600 1200 1800 2400 3000 3600 4200 48000

2

4

6

8

10

12

14

16

18

Pregabalin

GabapentinSte

ady

Sta

te C

Ste

ady

Sta

te C

max

max

(( μμ

g/m

L)g/

mL)

Mechanisms, Mechanisms . . .

Levetiracetam mechanism unknown

Zonisamide

Oxcarbazepine

Tiagabine

Topiramate

Lamotrigine

Gabapentin

X

X

Carbonic

Anhydrase

Inhibition

X

X

X

GABA

Potentiation

X

Glutamate

Antagonism

X

X

X

X

X

Ca2+ Channel

Blockade

X

X

X

X

Na+ Channel

Blockade AED

White HS. In: Pellock JM, Dodson WE, Bourgeois BFD, eds. Pediatric Epilepsy: Diagnosis and Therapy. 2nd ed. New York, NY:

Demos Medical Publishing Inc; 2001:301-316.

*Mechanism not clearly established.

X

X Pregabalin

Case: Barbara • 62 yr old medical assistant, DOA: 6/2/16, transferring patient

• Low back and left leg, posterior thigh, and calf pain

• Pain worse with sitting, heaviness with walking

• MSR: (R/L) Patella: 2+/2+, Med HS: 2+, 2-; Achilles: 2+/ 1+

Diagnosis:

Left L5/S1 radicular pain

Present Medications:

- gabapentin 200 mg QHS - tramadol 50 mg

TID

- amitriptyline 25 mg QHS - sertraline 50 mg

Recommendations:

Muscle Relaxants

Case: Alex

• 46 yr old with chronic low back pain. Referred to pain

management from primary care.

• History of axial low back pain and “back spasms” on and

off for 2 years with more persistent pain in lumbar spine

over last 6 months. “Nothing is working” and “I’m getting

worse”.

• Medications:

• Cyclobenzaprine 10 mg, 1 PO TID

• Nortriptyline 25 mg at night

• Hydrocodone/APAP 5/325, 3-4 per day

• Gabapentin 100 mg, 1 PO TID

42

Muscle Relaxers: Patterns of Use

• 85% took for back pain1

• Average length of use: 2.1 years1

• 44.5% took longer than 1 year1

• No difference in use patterns in those patients with

ambulatory impairment or lung disease1

• Benzodiazepine and muscle relaxer use associated with

fractures in elderly2

1. Dillon C, et al. Spine 2004;8:892-96.

2. Coutinho E, et al. BMC Geriatrics 2008;9:21.

“Muscle Relaxants”

44 Witenko, et al. PT.2014;39(6):427-435.

Agents by Mechanism of Action

CNS Depressants

Antihistamine: orphenadrine

Sedatives: carisoprodol, chlorzoxazone, metaxalone, methocarbamol

TCA-like: cyclobenzaprine

Central α Agonists

Tizanidine

GABA Agonists

Lioresal (Baclofen), benzodiazepines

Jackson K, Argoff C. Raj’s Practical Management of Pain, 4th ed.

Muscle Relaxers

Generic Name Staring dose Effective dose

Cyclobenzaprine Flexeril 5mg TID 10-20mg TID

Chlorzoxazone Paraflex,

Parafon

Forte

250 mg, 500

mg QID

250 mg, 500

mg QID

Orphenadrine Norflex 100 mg BID 100 mg TID

Carisoprodol Soma 350 mg TID 350 mg QID

Metaxalone Skelaxin 400 mg TID 800 mg TID

Methocarbomal Robaxin 500 mg QID 750 mg QID

Lioresal Baclofen 5mg TID 10-20 mg TID

Cyclobenzaprine HCl (Flexeril)

• FDA approved 1977 (5 mg,10 mg)1

• Animal studies2: via serotonin receptors at spinal level

to block alpha-mononeuronal excitation

• Relieves skeletal muscle spasm of local origin without

interfering with motor function

• Reduced or abolished skeletal muscle hyperactivity in

animal models

• CNS involvement at brain stem vs. spinal cord level

47 1. Cyclobenzaprine HCl PI, ALZA Corp, 2001.

2. Honda M, et al. Eur J Pharmacol. 2003;458:91-99.

Cyclobenzaprine (Flexeril) (5mg, 10mg)

• Similar to amitriptyline and imipramine

• Steady state within 3-4 days, plasma concentration

4X > than single doses

• ½ life = 18 hrs (range 8-37 hrs)

• “muscle spasm” dose: 5mg TID

• 2 studies for acute pain 2:

Result: 7 day treatment, by day 3, 78%-83% relief,

average 2 days earlier (30% reduction in time to

relief)

1. Cyclobenzaprine HCl PI, ALZA Corp, 2001.

2. Borenstein DG, Korn S. Clin Ther. 2003;25:1056-73.

Cyclobenzaprine: Meta-analysis

• Treated patients 5x as likely to report

symptom improvement by day 14 vs. placebo1

• Effect is greatest in first 4 days

• NNT: 2.7

• Effects size: 0.5

• Myofascial Pain2: (2 studies)

• Insufficient evidence

1. Browning R, et al. Arch Intern Med. 2001;161:1613-20

2. Leite et al. Cochrane Database 2009;3:CD006830.

Cyclobenzaprine HCl ER (Amrix)

Amrix (Cephalon): 15mg or 30mg Q day

Tmax: 8.1 hrs,

T1/2: 34 hrs

Results:

15 mg and 30mg effective in treating muscle spasm

associated with painful MSK conditions after 4 days

1. Malanga G, et al. Cur Med Res Opinioin 2009;251179-96.

2. Cyclobenzaprine ER/ Amrix package insert (Cephalon), 2009

Metaxalone (Skelaxin)

• FDA approved 19641

• “adjuvant therapy to rest,

PT, and other measures for

the relief of discomforts ”

• 400mg to 800 mg TID or

QID

• 69.6% vs. 17.4% marked

or moderate improvement

• Onset of action: 1 hr

• Peak levels: 2 hr

• Tmax: 4.3 h (fat meal); 3.3

h (fasting)

• Duration: 4-6 h

• Limited RPCs in MSK

conditions2

1. Fathie K. Curr Ther Res Clin Exp. 1964;6:677-83.

2. Dent RW, Ervin DK. Curr Ther Res Clin Exp 1975;18:433-440.

Methocarbamol (Robaxin)

• FDA approved 19641

• “adjuvant therapy to rest, PT, and other measures for

the relief of discomforts ”

• MOA: carbonic anhydrase, inhibition of NMDA?

• 500 mg or 750 mg PO QID

• Acute: 6,000 mg/day

• Maintenance: 4,000 mg/day

• IV available

• Limited RPCs in MSK conditions2

1. Methocarbamol

2. Tisdale SA, Ervin DK. Curr Ther Res Clin Exp 1975;17:525-530.

Carisoprodol (Soma)

• FDA approved in 1959

• Human evidence of muscle relaxation limited, animal

models possible block of descending reticular formation in

spinal cord1

• Dose: 350mg QID

• Soma vs. Butabarbital2:at 4 days, greater overall relief

• Metabolite: meprobamate (Schedule IV)

• SOMA scheduled in individual states

• 14 of 20: list of abused mood-altering substances2

1. Physicians’ Desk Ref, 58th ed, PDR, 2004.

2. Hindle TH, California Med. 1972;117:7-11.

3. Prescription Drug Addiction: http://www.addicusbooks.com/news_release_RxAddiction.htm

Abuse Potential: Soma

• n = 40, use of Soma for > 3 months, with/without history

of substance abuse

• Results: (with Hx substance abuse):

• 40% used in larger amounts than prescribed

• 30% used for an effect other than prescribed

• 10% used to augment effect of another med

• 20% attempted to obtain extra Soma prescription

• 10% used others, or obtained illegally

• All patients with Hx abuse: 65% used Soma in >1 of the

above

Reeves RR, et al. J Addict Dis. 1999;18:51-56.

Tizanidine

• Peak serum levels:1-5 hrs

• ½ life: 4-8 hrs

• Side effects: dry mouth, somnolence, hypotension,

bradycardia

• Renal impairment: clearance 50%

• Max dose 36 mg/day

• Muscle spasm1:tizanidine vs. diazepam (7D)

Greater lateral flexion

• Myofascial Pain2: titrated to 12 mg, improved pain, sleep,

pressure thresholds

1. Fryda-Kaurimsky Z. J Int Med Res. 1981:9:501-5.

2. Malange G, et al Pain Phys 2002;5:422-32.

Case: Alex

• 46 yr old with chronic low back pain. Referred to pain

management from primary care.

• History of axial low back pain and “back spasms” on and

off for 2 years with more persistent pain in lumbar spine

over last 6 months. “Nothing is working” and “I’m getting

worse”.

• Medications:

• Cyclobenzaprine 10 mg, 1 PO TID

• Amitriptyline 25 mg at night

• Hydrocodone/APAP 5/325, 3-4 per day

• Gabapentin 100 mg, 1 PO TID

56

Galer BS. Bonica’s Management of Pain. 2001

Topical vs. Transdermal Drug Delivery Systems

•Topical (lidocaine patch 5%)

•Peripheral tissue activity

•Applied directly over painful site

• Insignificant serum levels

•Systemic side effects unlikely

•Transdermal (fentanyl patch)

•Systemic activity

•Applied away from painful site

•Serum levels necessary

•Systemic side effects

Lidocaine Patch 5% • 10×14 cm, contourable, non-woven,

felt patch1

• Up to 3 patches applied to intact skin for up to 12 hours, daily

• 700 mg of aqueous-based lidocaine supplies analgesia without loss of sensation, 21 mg to skin

• Vehicle may cause “cooling effect” at the application site and provides a mechanical barrier for allodynic skin

• 2013 sales of $1.4 billion2

• Generic: Watson, Actavis

• NDA for lidocaine patch 1.8%, Sept 2015 1. Lidoderm patch 5%, PI.

2. IMS Data, 2013.

Diclofenac

Topical Diclofenac: FDA Approved (4 approved products in US)

1. Diclofenac epolamine patch (FLECTOR® Patch)1

• Indication: acute pain due to minor sprains, strains, & contusions

• BID

2. Diclofenac sodium gel (Voltaren® Gel)2

• Indication: relief of pain of OA of joints amenable to topical treatment, such as the knees & those of the hands

• QID

1. Flector Patch PI, Pfizer.

2. Voltaern Gel PI, Novartis 2009.

Topical Diclofenac: FDA Approved

3. Diclofenac 1.5% (Pennsaid)1

• approved 2009

• 40 drops to knee, 4 times/day (or 50 drops/ TID)

4. Diclofenac topical solution 2% (Pennsaid 2%)2

• Indication: pain of osteoarthritis of the knee

• More viscous than 1.5%

• 2 pumps (40 mg) BID

• Approved in 2014

62

1. Pennsaid PI, Covidien, 2009.

2. Pennsadi 2% PI, Horizon Pharma, 2015.

Diclofenac gel vs. Oral Diclofenac: Plasma Levels at Day 7 in Healthy Adults

• Lower plasma concentrations with Voltaren Gel • Cmax was 2 orders of magnitude lower than with oral tablets

• AUC was 1 order of magnitude lower than with oral tablets

*This is not an approved dose; maximum recommended dose is 32 g/day over all affected joints.

900

800

700

600

500

400

300

200

100

0

0 6 12 18 24

Pla

sm

a C

oncentr

ation

(ng/m

L)

Time (hours)

Diclofenac sodium tablets, 3 x 50 mg/day Voltaren Gel (2 knees, 2 hands), 4 x 12 g/day* Voltaren Gel (1 knee), 4 x 4 g/day

Data on file, Novartis Consumer Health Inc., Parsippany, NJ.

Menthol 5.7%,

Methyl Salicylate 6%

Camphor 1.2%

Menthol 1.4%

“Classical” TRP Channel Analgesics

0.75% capsaicin

10% menthol

30% methyl salicylate 30% methyl salicylate

10% menthol

4% camphor

TRPV1 TRPA1

TRPM8

TRPV1

TRPA1

TRPM8

66

When All Else Fails. . .

Effectiveness of Leech Therapy in OA Knee

•Medicinal leeches (Hirudo

medicinalis)

•Saliva: anti-inflammatory

substances, hyaluronidase

•Method:

• 4 leeches applied for

approx. 70 minutes

• Control: Diclofenac gel

300 g BID

Michalsen A et al. Ann Intern Med. 2003;139:724-730.

Post-Test #1

The proposed mechanism of action of

orphenadrine is:

a. Antihistamine CNS depressant

b. alpha agonist

c. GABA agonist

d. None of the above, mechanism of action

is unknown

Post-Test #2

FDA approved in the 1960s, this medication is

approved as an “adjuvant therapy to rest, physical

therapy, and other measures for the relief of

discomforts.”

a. Metaxalone

b. Tizanidine

c. Lioresal

d. None of the above, this FDA indication is

bogus

71

Summary

• Peripheral and central sensitization as a model to understand

chronic neuropathic pain and targets for pharmacotherapy

• Important targets include sodium channels, calcium, GABA,

and monoamine pathways

• Muscle relaxants as a class represent a heterogeneous group

of agents, awareness of mechanism of action may help to

better guide their use

• Many formulations developed many years ago, safety and

efficacy data is limited

• Understand mechanisms of action as approach used for

neuropathic and other pain conditions

• Some agents are limited by toxicities and potential for abuse

and misuse

THANK

YOU

steven.stanos@swedish.org