Dr. Yip

Wai

Man

Specialist in Geriatric medicine葉衛民醫生

老人科專科醫生

香港大學內外全科醫學士

英國皇家內科醫學院院士

香港內科醫學院院士

香港醫學專科學院院士(內科及老人科)

+ Chronic Pain is a common reasons for patients to seek medical  care, particularly elders.

+ Under‐treatment of pain is common+ Chronic pain can result in severe disability, reduced activity, sleep 

disturbance, depression and anxiety.+ 痛 苦+

Central sensitization of pain, defined as “an amplification of neural signaling within the CNS that elicits pain hypersensitivity”

+

Potentiation

of 5‐HT and NE activity in the CNS with

duloxetine

is  believed to result in pain inhibition and better outcome of pain

control

+

The onset of pain is a symptom of illness or  injury in the part of the body that is 

experiencing the pain.+

Acute pain gets a person's attention and 

prompts him or her to take action to prevent  further worsening of the condition causing the 

pain. + Chronic pain is pain that persists over time (6 

months or longer)

4

Brain image courtesy of Apollo

MedCom.Adapted from Woolf CJ. Ann Intern Med. 2004;140(6):441-451.

Used with permission from the American College of Physicians.

Noxious peripheral

stimuli

Nerve damage

No known tissue or

nerve damage

Inflammation

Acute

Nociceptive Pain

Inflammatory/Joint Pain

Neuropathic

Pain

Noninflammatory/ Non-neuropathic

Pain

Tissue damage

PresenterPresentation NotesPURPOSE OF THE SLIDEPresent an overview of a common pain classification system.

KEY POINTSPain may be classified in different ways—by its duration, by whether it is adaptive or maladaptive in terms of avoiding noxious stimuli, or by the type of stimulus inducing it. This classification is primarily based on the type of stimulus. Acute nociceptive pain may be defined as an adaptive, transient pain in response to a noxious stimulus. Diverse stimuli provoke a nociceptive response, including temperature (eg, burns or frostbite), chemicals (eg, acidic irritation), and mechanical pressure or abrasion (eg, crushing or cutting). Acute nociceptive pain is likened to an alarm that warns of potential danger. When acute nociceptive pain occurs, pain pathway structures are normal and function normally. Inflammatory/joint pain may be defined as spontaneous pain and hypersensitivity to pain in response to tissue damage and inflammation. Pain pathway structures appear normal, but they may not function normally, especially in joint-related pain.Neuropathic pain involves spontaneous pain and hyperalgesia in association with damage to, or lesion of, the nervous system (brain or spinal cord). This is analogous to an alarm that is constantly sounding, despite the fact that there is no emergency. This pain is maladaptive. Neuropathic pain is characterized by spontaneous pain and fluctuations in pain sensitivity to stimuli. Because the structural integrity of the pain pathways has been compromised, their function is abnormal as well.Noninflammatory/non-neuropathic pain results from abnormal central processing of normal input (eg, fibromyalgia, irritable bowel syndrome, tension-type headache, noncardiac chest pain). Noninflammatory/non-neuropathic pain is a type of maladaptive pain. In this case, pain pathways appear to have normal structure, but not normal function.

REFERENCEWoolf CJ. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med. 2004;140(6):441-451.

Acute Pain+

Is distinguished as being of recent 

onset, transient, and usually from  identifiable cause1

+ Acute reaction to injury or noxious  stimulous2,3

+ Short term, following an acute  event (e.g., surgery)3,4

+ Expected to end with healing3,4

+ Inflammation

Chronic Pain+

“Can be described as ongoing or 

recurrent pain, lasting beyond  the usual course of acute illness 

or injury or more than 3‐6  months”1

+ May involve changes in pain  processing and perception2,3

+ Central Sensitization

1.

ACPA. ACPA Consumer Guide to Pain Medication & Treatment, 2010:1‐81.2.

Marcus. In: Chronic Pain: A Primary Care Guide to Practical Management, 2009:37‐49.3.

National Pharmaceutical Council Inc. Pain: Current Understanding

of Assessment, Management, and Treatments, 2001:1‐101.4.

ICSI. Healthcare Guideline: Assessment and Management of Chronic

Pain, 2009:1‐91.

PresenterPresentation NotesKey Points:The slide highlights key characteristics to help differentiate chronic pain as a separate condition from acute pain.Acute pain typically occurs as a consequence of injury or trauma.2Acute pain serves an important biological function, as it warns of the potential for or extent of injury. In contrast to chronic pain, the pain resolves with healing of the underlying injury.3Chronic pain extends beyond the period of healing, with levels of identified pathology that often are low and insufficient to explain the presence and/or extent of the pain.3References:ACPA. ACPA Consumer Guide to Pain Medication & Treatment, 2010:1-81.Marcus DA. Physiology of Chronic Pain. Chronic Pain: A Primary Care Guide to Practical Management. New York, NY: Humana Press; 2009:37-49.National Pharmaceutical Council Inc. Pain: Current Understanding of Assessment, Management, and Treatments. Reston, VA: National Pharmaceutical Council and Joint Commission on Accreditation of Healthcare Organizations; 2001:1-101.ICSI. Healthcare Guideline: Assessment and Management of Chronic Pain, 2009:1-91.

+ Make your life bitter!+ Chronic pain is problematic because:

1.

We need more time to listen to our patients

2.

Most analgesics are ineffective and causing other  issues

3.

Patients developed depression, anxiety, and  medication non‐adherence problems

4.

Patients developed doctor shopping behavior

5.

Cost great burden to our aging society

+ Physiological ‐

a subjective symptom, no markers, imaging, no well  documentation possible

+ Cause of pain usually irreversible, e.g. OA, RA. 

+ Educational ‐

lack of it

+ Professional 

+ Regulatory/Legal ‐

Malpractice vs. DH investigation

+ Psycho‐Social ‐

“Don’t

complain!”, fear of addiction

+

Painful and debilitating conditions affecting ~116 million adults in the US and costing ~$635 billion per 

year in medical treatment and lost productivity1+ Decreased quality of life, functional impairment, 

economic burden, reduced independence+ Great unmet need for additional safe treatments for 

better pain control+ Similar overall treatment goals across diseases2,3

– Management of pain ‐

control and reduction– Education of patients and health care providers– Improvement in function and quality of life– Prevention and/or decrease in disability– Maintenance of work and activity

1.

Institute of Medicine. Relieving pain in America: A blueprint for transforming prevention, care, education, and research, 2011.2.

Zhang et al.

Osteoarthritis

Cartilage 2008;16(2):137‐62.3.

Diamond et al. Best

Pract Res Clin

Rheum

2006;20(4):707‐20.

PresenterPresentation NotesKey Points:Chronic pain affects an estimated 116 million American adults, which is more than the total affected by heart disease, cancer, and diabetes combined. Pain also costs the nation up to $635 billion each year in medical treatment and lost productivity.1The 2010 Patient Protection and Affordable Care Act required the Department of Health and Human Services (HHS) to enlist the Institute of Medicine (IOM) in examining pain as a public health problem.1 Osteoarthritis Research Society International (OARSI) recommendations: Twenty-five carefully worded recommendations have been generated based on a critical appraisal of existing guidelines; a systematic review of research evidence; and the consensus opinions of an international, multidisciplinary group of experts. The recommendations may be adapted for use in different countries or regions according to the availability of treatment modalities and strength of recommendation (SOR) for each modality of therapy.2Optimal management of patients with OA hip or knee requires a combination of non-pharmacological and pharmacological modalities of therapy. Recommendations cover the use of 12 non-pharmacological modalities: education and self-management; regular telephone contact; referral to a physical therapist; aerobic, muscle strengthening, and water-based exercises; weight reduction; walking aids; knee braces; footwear and insoles; thermal modalities; transcutaneous electrical nerve stimulation; and acupuncture. Eight recommendations cover pharmacological modalities of treatment: acetaminophen; cyclooxygenase-2 (COX-2) non-selective and selective oral non-steroidal anti-inflammatory drugs (NSAIDs); topical NSAIDs and capsaicin; intra-articular injections of corticosteroids and hyaluronates; glucosamine and/or chondroitin sulphate for symptom relief; glucosamine sulphate, chondroitin sulphate, and diacerein for possible structure-modifying effects; and the use of opioid analgesics for the treatment of refractory pain. Recommendations covering five surgical modalities: total joint replacements, unicompartmental knee replacement, osteotomy and joint preserving surgical procedures, joint lavage and arthroscopic debridement in knee OA, and joint fusion as a salvage procedure when joint replacement had failed.Although the above recommendations are developed for OA they are applicable to other choric pain states, including CLBP.References: Institute of Medicine. Relieving pain in America: A blueprint for transforming prevention, care, education, and research. National Academy of Sciences; 2011. [www.iom.edu/relievingpain]Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, Bierma-Zeinstra S, Brandt KD, Croft P, Doherty M, Dougados M, Hochberg M, Hunter DJ, Kwoh K, Lohmander LS, Tugwell P. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 2008;16(2):137-62.Diamond S, Borenstein D. Chronic low back pain in a working-age adult. Best Pract Res Clin Rheumatol 2006;20(4):707-20.

+ Pain is perceived in the brain– Ascending

nociceptive

pathways1

– Descending

modulatory

pathways2

+

Chronic pain associated with increased 

excitation and decreased inhibition of  pain pathways3,4

+

Serotonin

(5‐HT) and

norepinephrine

(NE) 

are key

modulatory

neurotransmitters in 

descending inhibitory pathways2,5,6

+

Potentiation

of 5‐HT and NE activity in 

the CNS is believed to result in pain  inhibition2,5,6

Cortex Lateral hypothalamusThalamusAmygdalaMedulla

Ascendingnociceptive pathways

Descendingmodulatory

pathways- 5-HT +/-- NE -

Aδ, c

Aβ

Nociceptor

GABAInterneuron

Pain perception symbols+ = facilitates-

= inhibits1. Iyengar et al. J Pharmacol Exp Ther 2004;311(2):576-84.2. Woolf. Ann Intern Med 2004;140(6):441-51.3. DeSantana et al. Curr Pain Headache Rep 2008;12(5):338-43.4. Staud R. Curr Rheumatol Rep 2011;13(6):513-20.

5. Richardson BP. Ann N Y Acad Sci 1990;600:511-19.6. Marieb et al. In: Human Anatomy & Physiology, 2007.

PresenterPresentation NotesImage: Applicable permissions and/or payment-for-use completed. Image created by Indegene, Inc. Iselin, NJ. Per agreement with Indegene, Lilly owns the final image as delivered and can use it in any way, for as long as needed. Contact at Indegene is Raviraj Devdas as of 14-May-2010.Key Points:There is considerable current and emerging literature about the pathophysiology and neurobiology of chronic pain. It is known that pain is perceived in the brain. Ascending nociceptive pathways transmit/conduct noxious stimuli from the peripheral regions of the body to the brain.1Descending modulatory pain pathways alter the processing of pain signals. These pathways receive contributions from multiple brain regions, including the periaqueductal gray matter and the periventricular nucleus of the hypothalamus. 2Chronic widespread pain results in changes in the central nervous system, which likely reflect alterations in supraspinal modulation of nociception, and include increases in excitatory and decreases in inhibitory modulation pathways. 3,4In the descending modulatory pain system, the neurotransmitters 5-hydroxytryptamine (5-HT) and norepinephrine (NE) modulate pain signals.2,5,65-HT both inhibits and facilitates the perception of pain. 5-HT inhibits pain via the descending inhibitory arm of the descending modulatory pathway and facilitates the perception of pain via the descending facilitatory arm of the descending modulatory pathway.5NE inhibits the perception of pain via the descending inhibitory arm of the descending modulatory pathway. NE does not seem to be involved in the facilitatory aspect of pain perception in the descending modulatory pathway.7References:Iyengar S, Webster AA, Hemrick-Luecke SK, Xu JY, Simmons RM. Efficacy of Cymbalta, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats. J Pharmacol Exp Ther 2004; 311(2):576-84.Woolf CJ; American College of Physicians; American Physiological Society. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med 2004 16;140(6):441-51.DeSantana J, Sluka KA. Central mechanisms in the maintenance of chronic widespread noninflammatory muscle pain. Curr Pain Headache Rep 2008;12(5):338-43.Staud R. Evidence for shared pain mechanisms in osteoarthritis, low Bback pain, and fibromyalgia. Curr Rheumatol Rep 2011;13(6):513-20.Richardson BP. Serotonin and nociception. Ann N Y Acad Sci 1990;600:511-9; discussion 519-20.Marieb EN, Hoehn K. The peripheral nervous system and reflex activity. In: Beauparlant S, eds. Human Anatomy & Physiology. 7th ed. San Francisco: Pearson Education, Inc; 2007:490-531.Jones. Descending noradrenergic influences on pain. Prog Brain Res 1991;88:381-94.

11

1.

Woolf

CJ. Pain. 2011;152(2

Suppl):S2-S15.2.

Mannion

RJ,

Woolf

CJ.

Clin J Pain. 2000;16(3

Suppl):S144-S156.3.

Latremoliere

A,

Woolf

CJ. J Pain. 2009;10(9):895-926.

•

Operationally defined as “an amplification of neural signaling within the CNS that elicits pain hypersensitivity”1

•

Features1-3

−

Development of or increases in spontaneous neural activity−

Reduced threshold for peripheral stimuli activation or dorsal horn neuron activation−

Increased receptive field of

nociceptive

afferents or dorsal horn neurons−

Increased response of dorsal horn neurons to painful stimuli

PresenterPresentation NotesPURPOSE OF THE SLIDEDiscuss key features of central sensitization.

KEY POINTSMultiple cellular processes lead to central sensitization. Central sensitization is not defined by activation of a single molecular pathway but rather represents the altered functional status of nociceptive neurons. During central sensitization, these neurons display 1 or all of the following: 1) development of or an increase in spontaneous activity; 2) reduction in threshold for activation; and 3) enlargement of nociceptive neuron receptive fields. These characteristics can be produced by several different cellular processes, including increases in membrane excitability, a facilitation of synaptic strength, and decreases in inhibitory transmission (disinhibition).1 Similarly, these mechanisms can be driven by different molecular effectors, including protein kinase A (PKA), protein kinase C (PKC), calcium/calmodulin-dependent protein kinase II (CAMKII), and extracellular signal-related kinase 1/2 (ERK1/2).1These kinases participate in changes in the threshold and activation kinetics of N-methyl-D-aspartate acid (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and in their trafficking to the membrane, cause alterations in ion channels that increase inward currents and reduce outward currents, and reduce the release or activity of γ-aminobutyric acid (GABA) and glycine.1Central sensitization can lead to shifts in the sensitivity of the pain system such that normally innocuous inputs can activate it and noxious inputs are exaggerated, prolonged, and spread widely. This can lead to sensory changes, including hyperalgesia and allodynia.2Extensive experimental medicine and clinical investigations over the past 20 years have revealed sensitization to be an important component of the pain hypersensitivity present in many patients.2

BACKGROUNDPotential mechanisms contributing to central sensitizationCellular processesDecreased inhibition1Increased membrane excitability1Synaptic facilitation1Microglial activation3Alterations in effectorsChanges in threshold and activation kinetics of NMDA and AMPA receptors1Changes in AMPA receptor membrane trafficking1Alterations in ion channels to increase inward currents and reduce outward currents1Reductions in the release or activity of GABA and glycine1Altered gene expression in dorsal horn neurons4

REFERENCESLatremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10(9):895-926.Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011;152(2 Suppl):S2-S15.Wieseler-Frank J, Maier SF, Watkins LR. Central proinflammatory cytokines and pain enhancement. Neurosignals. 2005;14(4):166-174.Mannion RJ, Woolf CJ. Pain mechanisms and management: a central perspective. Clin J Pain. 2000;16(3 Suppl):S144-S156.

Adapted from: Baron. Nat

Clin Pract 

Neurol

2006;2(2):95‐106.

Leading to:HyperalgesiaSpontaneous pain

(ongoing)Mechanical allodynia (tender points)

CNS Modulation

Synaptic PlasticityReorganization

PresenterPresentation NotesCymb00042177Copyright Disclosure: Image: Applicable permissions and/or payment-for-use completed. Abbreviations: CNS: central nervous system

Purpose of the Slide:To summarize the changes in the dorsal horn that occur with central sensitization. Key Points:As a consequence of peripheral nociceptor hyperactivity, dramatic secondary changes occur in the spinal cord dorsal horn.Due to the peripheral nociceptor hyperactivity, the multireceptive spinal cord dorsal horn neurons, which receive inputs from nociceptive C nerve fibers, as well as from non-nociceptive A nerve fibers, become hyperexcitable.Hyperexcitability is manifested by increased neuronal activity in response to noxious stimuli, expansion of neuronal receptive fields, and spread of spinal hyperexcitability to other segments.1This so-called central sensitization is initiated and maintained by activity in pathologically sensitized C-fibers, which sensitize spinal cord dorsal horn neurons by releasing glutamate, that acts on post synaptic N-methyl-D-aspartate (NMDA) glutamate receptors and the neuropeptide substance P.(/p102/col1/para2)Various symptoms relating to central sensitization are displayed that can coexist in a variety of combinations.(/p102/col1/para2-3;/col2/para1) Reference:Baron R. Mechanisms of disease: neuropathic pain--a clinical perspective. Nat Clin Pract Neurol 2006;2(2):95-106.

Adapted from: Scholz et al. Nat Neurosci 2002;5 Suppl:1062-7 and Baron. Nat Clin Pract Neurol 2006;2(2):95-106.

Diminished inhibition in the spinal dorsal horn is a  major contributor to chronic pain 

By decreaseddescending inhibition

NE

5-HTInhibitory

interneuron

By modified interneuron activity

Inhibitory

interneuron

PresenterPresentation NotesCymb00042177Copyright Disclosure: Image: Applicable permissions and/or payment-for-use completed. Abbreviations: 5-HT: serotonin, NE: norepinephrine

Purpose of the Slide:To explain how central disinhibition in the spinal dorsal horn is a major contributor to chronic pain. Key Points:Normal transmission is controlled by inhibitory neurons.1Spontaneous activity in C-fibers causes changes in central sensory processing that lead to hyperexcitability of the spinal cord dorsal horn neurons. This causes inputs from the mechanoceptive A-fibers to be perceived as pain.2Reduction in the synthesis of inhibitory neurotransmitters (γ-aminobutyric acid and glycine) or the loss of inhibitory interneurons, by excessive release of glutamate (an excitotoxic amino acid) due to peripheral nerve injury, leads to persistent spinal cord hyperexcitability and chronic pain.1 References:Scholz J, Woolf CJ. Can we conquer pain? Nat Neurosci 2002;5 Suppl:1062-7.Baron R. Mechanisms of disease: neuropathic pain--a clinical perspective. Nat Clin Pract Neurol 2006;2(2):95-106.

1.

Craig.

Annu

Rev

Neurosci

2003;26:1‐30.2.

Latremoliere

et al. J Pain 2009;10(9):895‐926.

IIIIII

IV

V

CA∂Aβ

Afferent Fibers

Peripheral sensitization and fiber recruitment

Hyperexcitability, lower threshold and greater sensitivity to pain

(hyperalgesia)

Recruited wide dynamic range cells now transmit pain signals, increasing

hyperalgesia

Reduction in inhibition of descendent modulation and number of

interneurons

Increase in the

supraspinal

stimulation leading to progressive increase in electrical response in the corresponding segment(Wind-up)

Pain in response to low thresholdafferents, even those not painful in nature

(allodynia) and spread of pain signal to other segments (secondary

hyperalgesia)

PresenterPresentation NotesThis figure was created by Primo Scientific Corporation for the use in GMSB slide sets.Key Points:Central sensitization is a complex neuroplastic process that can be viewed at various levels: intracellular, neurotransmitter, and circuitry. In this slide, the sequential steps that produce neuroplastic changes at the correspondent spinal segment are depicted:1 and 2: Peripheral sensitization due to a continuous nociceptive stimulus recruits more fibers apart from the traditional C for transmitting the excess nociceptive signals, thus rendering fibers that usually do not transmit pain as nociceptive transmitting fibers too.3 and 4: A and A fibers exert their second synapses in the wide dynamic range (WDR) dorsal horn neurons, thus recruiting more neurons to transmit pain signals. As a result, there is an increased transmission of nociceptive signals via ascendant pathways. The clinical translation of this result in hyperalgesia, and it renders the correspondent dorsal spinal segment with hyperexcitability and a lower threshold for pain signals.5: In time, this process makes the descendant modulation inhibition dysfunctional and the result is more excitability. Inhibitory interneuron trophism is jeopardized; and if the process evolves more in time, even apoptosis is described, making a worst scenario in terms of the inhibitory descendant influences.6: Wind-up is described when, to the already increased excitability, the supraspinal excitatory influences have no compensation on the descendant component. Central sensitization is a continuous process of dorsal horn hyperexcitability. 7: With the aforementioned physiopathologic process and with a low threshold established, afferences of a non-nociceptive nature are transmitted as painful, thus making the brain interpret them as pain, and allodynia is the clinical translation. When this process is extended to adjacent spinal segments, the original pain zone enlarges, thus being translated clinically as secondary hyperalgesia.Hyperalgesia, allodynia, and secondary hyperalgesia are the clinical symptomatology of central sensitization.With chronic evolution, this process may establish the necessary neuroplastic changes for beginning to produce the pain signal at the dorsal horn level and thus, making the pain signal independent of the original stimulus.References:Craig AD. Pain mechanisms: labeled lines versus convergence in central processing. Annu Rev Neurosci 2003;26:1-30.Latremoliere A, and Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain 2009;10(9):895-926.

Mannion

et al.

Clin

J Pain 2000;16(3

Suppl):S144‐56.

Substance P

Sensory Input

NK-1R AMPAR NMDAR

No

stimulus

No output to brain

NO PAINNO PAIN

A

Output of Pain Projection Neuron

Glutamate

Proportional transmission of information to brain

NOCICEPTIVE PAINNOCICEPTIVE PAIN

Low-intensity stimulusB

NK-1R AMPAR NMDAR NK-1R AMPAR NMDAR

ACTIVITYACTIVITY--DEPENDENT FACILITATIONDEPENDENT FACILITATION

High-intensity stimulus

Exaggerated response with non-proportional increase in transmission of information to the brain

C

PresenterPresentation NotesThis figure was created by Primo Scientific Corporation for the use in GMSB slide sets.Abbreviations: AMPAR: AMPA receptor, KAR: kainate receptor, NK-1R: NK-1 receptor, NMDAR: NMDA receptorKey Points:This figure introduces the concept that central sensitization, much like peripheral sensitization (defined as a reduction in the threshold of nociceptive efferent receptors, caused by a local change in the sensitivity of sensory fibers initiated by tissue damage), is a form of neuroplasticity within the pain system that renders dorsal horn neurons hyperexcitable.In the figure above, condition A represents the absence of a noxious stimulus; thus C fibers are quiescent and dorsal horn neurons are not activated. In figure B, a low-intensity noxious stimulus activates C fibers that release glutamate. Glutamate binds to the AMPA receptors located post-synaptically on the dorsal horn neuron, causing the neuron to fire. In figure C, a high-intensity stimulus causes C fibers to release both glutamate and neuropeptides. These neurochemicals generate slow synaptic currents post-synaptically that summate to produce the (transient) wind-up phenomenon and (a long-lasting phenomenon) central sensitization (via post-translational modifications). In this way, the output of the dorsal horn neuron is augmented or enhanced. Wind-up may be induced by the repetitive firing of C fibers which fire under conditions of severe and persistent injury which produces subsequent release of glutamate and/or substance P2AMPA receptors and NMDA receptors are two types of glutamate receptors that are found on dorsal horn neurons. Activation of the AMPA receptor allows the influx of cations (sodium, potassium, calcium) that help to depolarize the dorsal horn neuron. Once threshold is reached, the magnesium block on the NMDA receptor is relieved and the receptor may be activated by the binding of glutamate.2Upon NMDA receptor activation, a further influx of calcium into the dorsal horn neuron may be observed. Calcium (external or from intracellular stores) has the potential to activate COX-2 and nitric oxide (NO) to stimulate the production of prostaglandins. Additionally, NO and prostaglandins contribute to neural and glial cell plasticity (apoptosis, axonal sprouting, and new afferent connections). These neurochemicals also contribute to sensitization within the dorsal horn neurons by reducing the threshold for neuronal activation.3One effect of sensitization is that dorsal horn neurons may now be activated by formerly innocuous stimuli (Aβ fibers or the “non-nociceptors” usually transmit this information). These formerly innocuous stimuli now have the ability to produce pain. Furthermore, there can also be an exaggerated response to noxious stimuli (hyperalgesia), and a spread of sensitivity to non-injured areas.2 Later stages of central sensitization are sustained by transcriptional changes in the dorsal horn neuron.2Other mechanisms that may contribute to central sensitization include increased tone in the descending neural pathways that augment pain,4 activation and migration of glial cells into the spinal cord with release of inflammatory cytokines and glutamate,5 and changes in the thalamus and primary somatosensory cortex.6ReferencesMannion RJ, Woolf CJ. Pain mechanisms and management: a central perspective. Clin J Pain 2000;16(3 Suppl):S144-56.Basbaum AI, Jessell TM. The perception of pain. In: Kandel ER, Schwartz JH, Jessell TM, eds. Principles of Neural Science. 4th ed., St. Louis, MO;: McGraw Hill; 2000:479.Vadivelu N, Sinatra R. Recent advances in elucidating pain mechanisms. Curr Opin Anaesthesiology 2005;18(5):540-7.Ossipov MH, Lai J, Malan TP Jr, Porreca F. Spinal and supraspinal mechanisms of neuropathic pain. Ann NY Acad Sci 2000;909:12-24.Wieseler-Frank J, Maier SF, Watkins LR. Central proinflammatory cytokines and pain enhancement. Neurosignals 2005;14(4):166-74.Guilbaud G, Benoist JM, Levante A, Gautron M, Willer JC. Primary somatosensory cortex in rats with pain-related behaviours due to a peripheral mononeuropathy after moderate ligation of one sciatic nerve: neuronal responsivity to somatic stimulation. Exp Brain Res 1992;92(2):227-45.

1.

Beydoun and Backonja. J Pain Symptom Manage 2003;25(5 Suppl):S18‐30.2.

Raskin et al. Pain Med 2006;7(5):373‐85.

3. Argoff et al. Mayo Clin Proc 2006;81(4 Suppl):S12-25.4. Cole. Pain Medicine 2007;8(Suppl 2):S27-S32.

Spinal  Cord

Na+

channel modulators•Carbamazepine •Oxcarbazepine•TCAs•Topiramate •Lamotrigine•Lidocaine

Peripheral sensitization Central sensitization

Descending inhibitory pathways

(NE/5-HT,

enkephalins)

TCAs, SNRIs, SSRIsα-adrenergic

blocking agentsOpioidsTramadolCannabinoids

Ca2+ channel modulators•

Gabapentin•

Levetiracetam•

Oxcarbazepine

•

Lamotrigine•

Pregabalin

NMDA

antagonists•

Ketamine•

Dextromethorphan•

Methadone•

Memantine

PresenterPresentation NotesCymb00042177Copyright Disclosure: Image: Applicable permissions and/or payment-for-use completed. Adapted from Snell RS. Introduction and Organization of the Nervous System. Clinical Neuroanatomy. 6th ed. Philadelphia: Lippincott Williams & Wilkins;2006:1-30.Abbreviations: NE: norepinephrine, 5-HT: serotonin, SNRI: selective norepinephrine reuptake inhibitor, SSRI: selective serotonin reuptake inhibitor, TCA: tricyclic antidepressant, NMDA: N-Methyl-D-aspartate

Key Points:Multiple mechanisms may play a role in chronic pain conditions, such as fibromyalgia.Some of these pain mechanisms involve changes in peripheral neurons (peripheral sensitization, ectopic excitability), while other mechanisms involve changes in the central nervous system (CNS). Ectopic excitability, structural reorganization, and decreased inhibition are unique to neuropathic pain. Peripheral and central sensitization may contribute to other types of pain, but they play a role in neuropathic pain as well.5The neurotransmitters 5-HT and NE have been implicated in the modulation of endogenous analgesic mechanisms via the descending inhibitory pain pathways in the brain and spinal cord. In pathologic pain states, these endogenous pain inhibitory mechanisms may be dysfunctional. This may contribute to the central sensitization and hyperexcitability of the spinal and supraspinal pain transmitting pathways that may manifest as persistent pain.2

Background:Agents used in the treatment of neuropathic pain can be stratified into three groups1 according to their major putative antineuralgic mechanisms of action. Drugs that modulate peripheral sensitization by way of their effects on the sodium channels (Eg, carbamazepine, oxcarbazepine, topiramate etc.)Drugs that enhance the descending inhibitory pathways from the brain stem to the spinal cord (Eg, Tramadol, desipramine, venlaflaxine etc.)Drugs that modulate central sensitization (Eg, Gabapeptin, pregabalin, memantine etc.)Other drugs include capsaicin, which works by depleting substance P from the peripheral C nociceptors; nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase 2 (COX-2) inhibitors, which partially exert their effect by inhibiting COX; and levodopa, whose mechanism of action is unknown.1

References:Beydoun A, Backonja MM. Mechanistic stratification of antineuralgic agents. J Pain Symptom Manage 2003;25(5):S18-30.Raskin J, Wang F, Pritchett YL, Goldstein DJ. Duloxetine for patients with diabetic peripheral neuropathic pain: a 6-month open-label safety study. Pain Med 2006;7(5):373-85.Argoff CE, Backonja MM, Belgrade MJ, Bennett GJ, Clark MR, Cole BE, Fishbain DA, Irving GA, McCarberg BH, McLean MJ. Consensus guidelines: treatment planning and options. Diabetic peripheral neuropathic pain. Mayo Clin Proc 2006;81(4 Suppl):S12-25. Erratum in: Mayo Clin Proc 2006;81(6):854.Cole BE. Diabetic peripheral neuropathic pain: recognition and management. Pain Med 2007;8 Suppl 2:S27-32.Woolf CJ; American College of Physicians; American Physiological Society. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med 2004 16;140(6):441-51.

+

Screening, assessing, and documenting pain  routinely is an important first step in assuring 

that unrelieved pain is identified and treated  promptly

+ Screening for pain can be administered  quickly for most patients on a routine basis.

+

Prompt intervention, and follow‐up  evaluation of the pain and the effectiveness of 

treatment are important components of pain  management.

17

+ OA knees+ Chronic Low Back Pain+ Fibromyalgia+ Diabetic neuropathy

Chronic OA Pain

Chronic Low Back Pain

1. Wolfe et al. Arthritis Rheum 1990;33(2):160-72.2. Staud and Rodriguez. Nat Clin Pract Rheumatol 2006;2(2):90-8

•

OcciputSuboccipital

muscleinsertions

•

TrapeziusMidpoint of the upper border

•

SupraspinatusAbove the scapula spinenear the medial border

•

Greater

trochanterPosterior to thetrochanteric

prominence

•

GlutealUpper outer quadrantsof the buttocks

•

Low cervicalAnterior aspects of theintertransverse

spacesat C5-C7

•

Second ribSecond

costochondraljunctions

•

Lateral epicondyle

2 cm distal tothe

epicondyles

•

KneeMedial fat pad proximalto the joint line

PresenterPresentation NotesCymb00042177Copyright Disclosure: Image: Applicable permissions and/or payment-for-use completed.

Key Points:Digital palpation on these sites is performed with an approximate force of 4 kg using the thumb pad. Whitening of the nail bed usually occurs upon exerting a pressure of ~4 kg.1(/p171/table8)2(/p91/col2/box1)For a tender point to be considered positive, the patient must state that the palpation was painful.1(/p171/Table8)At least 11 of the 18 sites must be positive for the tender point criterion to be met.1(/p171/Table8)

Background:The ACR study included 558 patients (293 with fibromyalgia, 265 control patients with other chronic pain conditions). Controls were matched with fibromyalgia patients for age and sex.1(/p162/col1/para4)(/p167/table5)(/p170/Table7)The combination of widespread pain and mild or greater tenderness in 11 or more of the 18 tender point sites yielded a sensitivity of 88.4% and specificity of 81.1% for the diagnosis of fibromyalgia.1(/p168/table6) (/p170/Table7)Although the ACR criteria are the currently accepted standard for research settings, their clinical usefulness is a subject of debate. As patients with fibromyalgia tend to experience tenderness throughout the body, clinicians question the specific designation of 18 tender points. There is some question as to how often all 18 tender points are examined in clinical practice settings and if examining less than 18 tender points makes the diagnosis of fibromyalgia invalid. Practitioners also question whether the criteria need to include other associated symptoms.3(/p386/col1/para2;/col2/para1,/para2)

References:Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P, et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 1990;33(2):160-72.Staud R, Rodriguez ME. Mechanisms of disease: pain in fibromyalgia syndrome. Nat Clin Pract Rheumatol 2006;2(2):90-8.Häuser W, Eich W, Herrmann M, Nutzinger DO, Schiltenwolf M, Henningsen P. Fibromyalgia syndrome: classification, diagnosis, and treatment. Dtsch Arztebl Int 2009;106(23):383-91.

21

1.

Creamer et al. Lancet

1997;350(9076):503‐8.2.

Zhang et al.

Osteoarthritis

Cartilage 2008;16(2):137‐62.

Intra

-artic

ular s

teroid

s/hya

luron

ic

acid/

topic

al NS

AID

Surgery

Prescription NSAID

Over-the-counter NSAID

Acetaminophen

Patient educationWeight reduction

Exercise, physical therapy,

assistive

devices

OpioidsDuloxetine

PresenterPresentation NotesAbbreviations: OA: osteoarthritis, NSAID: non-steroidal anti-inflammatory drug Key Points:Treatment should be individualized and based on the distribution and severity of joint involvement as well as the presence of comorbid conditions.Education of patients, social support, and counseling are often beneficial.Physical therapy has an important role in the management of patients with osteoarthritis.It is important for the practitioner to recognize that layers of the pyramid are added one to another in a stepwise fashion during the course of managing the individual patient (eg, NSAID can be added on in lower dosages to a regimen consisting of paracetamol and topical capsaicin, or intra-articular corticosteroid injections can be given to patients already on paracetamol, NSAID, or both).Although this algorithm was developed for OA pain, it can, to some extent, be applied to chronic pain treatment in general.References:Creamer P, Hochberg MC. Osteoarthritis. Lancet 1997;350(9076):503-8.Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, Bierma-Zeinstra S, Brandt KD, Croft P, Doherty M, Dougados M, Hochberg M, Hunter DJ, Kwoh K, Lohmander LS, Tugwell P. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 2008;16(2):137-62.

+ Risk of liver toxicity at > 4g/day in healthy patients+ Caution in alcoholics and liver disease+ >100 APAP combinations on the market (e.g.,

opioids, antihistamines)+ Caution with combination forms

– e.g.,

Neozep, Flu‐off….

System

Adverse Event

Caution

GASTROINTESTINAL

Mucosal ischemia

Avoid in elderlyGastric/Duodenal ulceration

Avoid in ulcer patientsPerforation/strictures 

Limit chronic use RENAL

Renal

hypoperfusion/ARF

Avoid in renal disease

Interstitial nephritis

Avoid in heart failure

Papillary necrosis

Avoid in CADSodium/fluid retention (K)

Avoid in diabetesHypertension/Edema

CARDIAC

AMI

Limit dose/duration

HEPATIC

Liver failure

Avoid in liver disease

HEMATOLOGIC

Bleeding

Avoid with anticoagulants

+ Well‐tolerated & effective in many acute & chronic pain  states

– Musculoskeletal

pain, OA/RA, dental pain,

dysmenorrhea

+ Effective in incidental pain; long duration of action

+ Treats pain that

opioids

don’t

treat well

+ Reliable & predictable: less inter‐patient dose variability

+ Analgesic ceiling effect

+ Balanced analgesia in acute or chronic pain

+ A weak μ‐opioid

receptor agonist and adrenergic

reuptake inhibitor

+ Effective in

musculoskeletal

pain such as fibromyalgia, and

neuropathic

pain

+ Alternative for patients contraindicated to NSAIDs

•

Bjordal

JM, et al. European Journal of Pain. 2007;11:125–138.•

In a pooled analysis of

duloxetine

in studies in OA (including all randomized NSAID nonusers in OA-1 and OA-2), the difference between active drug and placebo was 7.9 (95% CI, 2.3-13.5) on a 100-mm VAS:

Data on File, Eli Lilly and Company. (2011). 27

PresenterPresentation NotesBjordal JM, et al. Short-term efficacy of pharmaco therapeutic interventions in osteoarthritic knee pain: A meta-analysis of randomised placebo-controlled trials. European Journal of Pain. 2007;(11):125–138.

+ Duloxetine

is a

serotonin‐norepinephrine reuptake inhibitor (SNRI)1,2

+

Duloxetine’s analgesic effects are  independent of its central antidepressant 

effects3

+

Preclinical

models of central sensitization  suggest the efficacy of

duloxetine

in the 

treatment of persistent or chronic pain11. Iyengar et al. J Pharmacol Exp Ther 2004;311(2):576-84.2. Bymaster et al. Curr Pharm Des 2005;11(12):1475-93.3. Perahia et al. Int Clin Psychopharmacol 2006;21(6):311-7.

PresenterPresentation NotesCymb00054970Abbreviations: 5-HT: serotonin, NE: norepinephrine

Key Points:Duloxetine is a dual reuptake inhibitor of 5-HT and NE (serotonin-norepinephrine reuptake inhibitor [SNRI]).1(/p577/col1/para3), 2 (p1487/col1/para1)5-HT and NE are key mediators of descending pain pathways and offer a highly effective alternative for the treatment of persistent pain states in humans.1(/p576/col1/para1)(/p583/col1/para3)While some degree of pain relief would be expected to accompany improvement of mood in patients with depression, duloxetine is clearly exerting a direct and specific analgesic effect independent of its antidepressant effect.3(/p316/col1/para3)Preclinical models of central sensitization suggest the efficacy of duloxetine in the treatment of persistent/chronic pain.1(/p581/col2/para2)

References:Iyengar S, Webster AA, Hemrick-Luecke SK, Xu JY, Simmons RM. Efficacy of duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats. J Pharmacol Exp Ther 2004;311(2):576-84.Bymaster FP, Lee TC, Knadler MP, Detke MJ, Iyengar S. The dual transporter inhibitor duloxetine: a review of its preclinical pharmacology, pharmacokinetic profile, and clinical results in depression. Curr Pharm Des 2005;11(12):1475-93.Perahia DG, Pritchett YL, Desaiah D, Raskin J. Efficacy of duloxetine in painful symptoms: an analgesic or antidepressant effect? Int Clin Psychopharmacol 2006;21(6):311-7.

1. Cymbalta [package insert]. 2012. 2. Steeds. Surgery 2009;27(12):507-11.3. Fields et al. In: Wall and Melzack’s Textbook of Pain. 5th ed. UK; 2006:125-142.

In the spinal cord – 5-HT and NE are

believed to act via descending pain pathways to reduce perception of pain by dampening pain signals ascending to the brain from the dorsal horn2,3

Although the exact mechanism of the analgesic action of

duloxetine

in humans is unknown, it is believed to be related to the

potentiation

of

serotonergic

and

noradrenergic

activity in the CNS1

Peripheralnociceptor

Dorsal horn

Ascending pathwayDescending pathway

Brain

PresenterPresentation NotesCymb00054970Copyright: Image: Applicable permissions and/or payment-for-use completed. Abbreviations: CNS: central nervous system, 5-HT: serotonin, NE: norepinephrine

Key Points:Although the exact mechanism of the analgesic action of duloxetine in humans is unknown, it is believed to be related to the potentiation of serotonergic and noradrenergic activity in the CNS.1(/p21/para5)5-HT and NE neurons are involved in a well-described pain-modulating circuit that includes the amygdala, periaqueductal gray (PAG), dorsolateral pontine tegmentum (DLPT), and rostral ventromedial medulla (RVM), and may inhibit ascending pain signals via descending pathways.4(/p576/col1/para1;/col2/para2)In the spinal cord, 5-HT and NE are believed to act via descending pathways, synapse on the dorsal horn nerves, and reduce perception of pain by dampening pain signals ascending to the brain from the dorsal horn.2(/p509/col2/para2)(/p508/Figure1)

Background:5-HT and NE released in this circuit modify the pain signals at the level of the dorsal horn in the spinal cord. NE pathways result in inhibitory activity in the dorsal horn, whereas the 5-HT brainstem pathways can result in both facilitatory and inhibitory activities.5(/p384/col2/para1)6(/p517/para3)(/p518/para2)

References:Cymbalta [package insert]. Indianapolis, USA: Eli Lilly and Company; 2012. Available at: http://pi.lilly.com/us/cymbalta-pi.pdf. Last accessed: 9 Apr, 2013.Steeds CE. The anatomy and physiology of pain. Surgery 2009;27(12):507-11. Available at: http://www.surgeryjournal.co.uk/article/S0263-9319(09)00253-1/abstract. Last accessed: 9 Apr, 2013.Fields HL, Basbaum AI, Heinricher MM. Central nervous system mechanisms of pain modulation. In: McMahon SB, Koltzenberg M, editors. Wall and Melzack’s Textbook of Pain. 5th ed. London, UK:Elsevier, Churchill, Livingston; 2006:125-142.Iyengar S, Webster AA, Hemrick-Luecke SK, Xu JY, Simmons RM. Efficacy of duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats. J Pharmacol Exp Ther 2004;311(2):576-84. Jones SL. Descending noradrenergic influences on pain. Prog Brain Res 1991;88:381-94. Richardson BP. Serotonin and nociception. Ann N Y Acad Sci 1990;600:511-19.

+ Duloxetine

is highly bound to human plasma proteins  (>90%)1,4

+ Elimination half‐life ~12 hours in plasma  (range: 8‐17 hours)1,4

+ Pharmacokinetics

are dose proportional over the therapeutic  range2,4

+ Dose adjustments are not dependent on3,4

– Age, gender, and/or smoking– Ethnic origin– Renal impairment (mild or moderate)

1.

Smith et al.

Vasc

Health Risk

Manag

2007;3(6):833‐44.2.

Sharma et al. J

Clin Pharmacol

2000;40(2):161‐7.

3.

Lobo et al.

Clin Pharmacokinet

2009;48(3):189‐97.4. Cymbalta [package insert]. 2012.

PresenterPresentation NotesCymb00054970[Source: Smith et al. Vasc Health Risk Manag 2007;3(6):833-44. Pg 835, Col 2, Paras 3-4]Abbreviation: 5-HT: serotonin

Key Points:Duloxetine is classified as a selective serotonin-norepinephrine reuptake inhibitor (SNRI).1(/p834/col2/para3)It is highly bound to plasma proteins (>90%).1(/p835/col2/para3)

Background:Duloxetine is a selective inhibitor of both 5-HT and norepinephrine (NE) reuptake, and is classified as a selective SNRI.1(/p834/col2/para3)It is highly bound to plasma proteins (>90%) and has an elimination half-life of about 12 hours in plasma (range: 8-17 hours).1(/p835/col2/para3-4)The pharmacokinetics of duloxetine are dose proportional over the therapeutic range.2(/p167/col1/para4)Duloxetine can be administered to patients being treated for fibromyalgia without regard to age, sex, ethnic origin, smoking status, or renal impairment (mild or moderate) over the recommended dose range.3(/p197/col1/para1)

References:Smith T, Nicholson RA. Review of duloxetine in the management of diabetic peripheral neuropathic pain. Vasc Health Risk Manag 2007;3(6):833-44.Sharma A, Goldberg MJ, Cerimele BJ. Pharmacokinetics and safety of duloxetine, a dual-serotonin and norepinephrine reuptake inhibitor. J Clin Pharmacol 2000;40(2):161-67.Lobo ED, Quinlan T, O’Brien L, Knadler MP, Heathman M. Population pharmacokinetics of orally administered duloxetine in patients: implications for dosing recommendation. Clin Pharmacokinet 2009;48(3):189-97.Cymbalta [package insert]. Indianapolis, USA: Eli Lilly and Company; 2012. Available at: http://pi.lilly.com/us/cymbalta-pi.pdf. Last accessed: 9 Apr, 2013.

*p≤.05, **p≤.01, ***p≤.001 vs. placebo

LOCF: last observation carried forward, MMRM: mixed‐effects model repeated measures1. Arnold et al. Arthritis Rheum 2004;50(9):2974-84.2. Data on file, Eli Lilly and Company.

Baseline toEndpoint2

LOCF

LS M

ean

Cha

nge

Impr

ovem

ent

Weeks on Study Drug2

****

***

***

*

MMRM

PresenterPresentation NotesCymb00054970Study Code: Study 1: HMBO[Source: HMBO Study Report:2 Pg 218, Table 14.3.18; LOCF: Pg 92, Table HMBO.11.13.]Abbreviations: BPI: Brief Pain Inventory, LOCF: last observation carried forward, LS: least squares, MMRM: mixed-effects model repeated measures

Key Points:Although the BPI was not the primary outcome in Study 1, it is shown here for comparison with results in subsequent duloxetine fibromyalgia studies. The BPI was a secondary measure in Study 1 per protocol and was analyzed using both the MMRM and analysis of covariance (ANCOVA) model (LOCF analysis) as stated in the protocol. 1(/p2976/col2/para3)(/p2977/col1/para4)2(/p35/Table5)(/p218/table 14.3.18)(/p8/para2)(/p230/table14.3.19)Compared with placebo, duloxetine 60 mg BID significantly reduced BPI 24-hour average pain score at Weeks 1, 2, 4, and 12 by MMRM analysis. 2(/p218/Table HMBO.14.3.18)Compared with placebo, duloxetine 60 mg BID significantly reduced BPI 24-hour average pain score from baseline to endpoint using the ANCOVA model (LOCF analysis) (far right side of figure).2(/p92/Table HMBO.11.13)

Background:Study 1 was a Phase 2 proof-of-concept study. In this study, duloxetine was dosed as 60 mg twice daily, that is, a total daily dose of 120 mg/day.

References:Arnold LM, Lu Y, Crofford LJ, Wohlreich M, Detke MJ, Iyengar S, Goldstein DJ. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum 2004;50(9):2974-84.F1J-MC-HMBO study. Data on file, Eli Lilly and Company.

Pooled data from 4 studies: Mean change baseline to endpoint (SD)Arnold et al. Prim Care Companion J Clin Psychiatry 2009;11(5):237-44.

36-item Short-Form Health Survey (SF-36)MeasureSF-36 Scores

Placebo N = 489

DLX 60-120 N = 717/723 p-value

Mental component 1.63 (0.45) 4.6 (0.39)

Values reported in 0-10 scale

Flare ↓

33Tapentadol

AUS Assessment Report;

Afilalo

et al. 2010;

DeLemos, et al. 2010;

Lehmann

et al. 2005;

Markenson

JA et al. 2005;

Tannenbaum

et al. 2004

Duloxetine

NSAID nonusers only

PresenterPresentation Notes

+

In a pooled analysis of

duloxetine

in studies in CLBP 

(CLBP‐1, CLBP‐2, and CLBP‐3),  the difference between 

active drug and placebo was  6.2 (95% CI 3.5‐8.9) on a 100‐ mm VAS2

In parentheses ‐

number of trials; total number of participants 

1. Machado et al. Rheumatology (Oxford) 2009;48(5):520-7.2. Data on File, Eli Lilly and Company. (2011).

Electropuncture

(1;25)Immunoglobulins

(1;41)Infrared (1;38)Vit

B12 (1;60)Neuroreflexotherapy

(1;70)Acupuncture (4;149)

Heat wrap (2;255)TENS (4;178)

Nerve blocks (1;17)Back school (1;26)

Anticonvulsants (1;96)Muscle relaxants (9;820)

Massage (1;51)Laser (2;76)

Facial injections (3;257)Herbal meds (4;705)

RF degeneration (4;223)Analgesics (3;748)

Magnets (1;36)NSAIDs

(7;1349)SMT (6;247)ATP (1;161)

Behavioral (2;34)Antidepressants (4;217)

Exercise (3;204)Prolotherapy

(3;263)PT (1;120)

Traction (1;150)

Radiotherapy (1;32)PTIT (3;139)

ISIs(1;116)Shortwave

(1:65)NMDA antagonists(1;43)

Colchicine

(1;15)

Favors Treatment

Favors Placebo

Analgesic Efficacy (100-point scale)

-50 -40 -20 0 20 40 50-30 -10 10 30

Effect Over Placebo1

PresenterPresentation Notes[Source: SDD: /lillyce/prd/ly248686/integrations/cpse/programs_stat/tfl_output/lobpia14.rtf, pg 3]This figure was created by Primo Scientific Corporation for the use in GMSB slide sets.Abbreviations: CLBP: chronic low back pain, VAS: Visual Analog Scale, CI: confidence interval, ATP: adenosine triphosphate; ISIs: Intradiscal steroid injections; NMDA: N-methyl-D-aspartate, PTIT: percutaneous thermocoagulation intradiscal techniques; RF: radiofrequency; SMT: Spinal manipulative therapy; TENS: transcutaneous electrical nerve stimulation

Key Points:CLBP is difficult to treat and a myriad of treatments have been tried.In this graph showing meta-analysis of efficacy (on pain) of various interventions in chronic low back pain, it can be seen that the difference between active drug and placebo is in the order of 0-35 mm on a 100-mm VAS.Note that efficacy data for many of these treatments were from only 1 trial and/or a small number of patients, so comparisons are problematic. That is not the case at least with opioid analgesics, NSAIDS, muscle relaxants and antidepressants, where data are coming from a larger number of trials.For duloxetine (not shown on this graph), this difference between active drug and placebo is 6.2 (95% CI 3.5-8.9) (Data on file). This is based on the pooled analysis of mean change from baseline to LOCF endpoint in BPI average pain in 3 CLBP studies (all randomized patients from CLBP-1, CLBP-2, and CLBP-3, Excluding duloxetine 20 mg group).The 3 CLBP studies were multicenter, randomized, placebo-controlled trials to assess the efficacy and safety of duloxetine in patients with CLBP. The placebo-controlled treatment phase in CLBP-1 and CLBP-2 were 13 weeks, while in CLBP-3 it was 12 weeks.CLBP-1 = HMEN, CLBP-2 = HMEO, CLBP-3 = HMGCReference:Machado LA, Kamper SJ, Herbert RD, Maher CG, McAuley JH. Analgesic effects of treatments for non-specific low back pain: a meta-analysis of placebo-controlled randomized trials. Rheumatology (Oxford) 2009;48(5):520-7.

Class Pain Related Efficacy

Breadth across pain

Safety and Tolerability

Other

NSAIDS/COX2s •

Effective in mild non-Neuropathic

pains (30-50% pain reduction)

•

Shown to be ineffective in

Neuropathic

pain•

Ineffective in more moderate or severe pain

•

Not for long term use• CV risk• Serious GI effects• Vioxx

stigma

•

Anti-Inflammatory effects•

NSAIDs

are affordable

Anticonvulsants •

30-50% pain reduction•

Gold standard in

Neuropathic

pain

•

Proven in

Neuropathic

pain and

Fibromyalgia

•

Benefit of no drug-

drug interactions•

Weight gain, edema, sedation and cognitive dulling

• Long

titrations•

Complicated dosing•

Not well tolerated in the elderly•

Adverse event on sleep is perceived as a benefit

Duloxetine •

30-50% pain reduction•

Effective in mild, moderate, and severe patients

•

Effective across multiple Chronic conditions: DPNP, FM, LBP and OA•

Neuropathic

and Inflammatory conditions

•

No TCA-like side effects• Nausea

•

Effective in MDD and GAD•

Not effective for sleep (non-sedative)

35

Class Pain Related Efficacy

Breadth across pain

Safety and Tolerability

Other

Tramadol •

Effective in mild-

severe pain• Unpredictable

•

Mixed results in OA and CLBP

• Opioid

like effects •

Does not have

opioid

stigma• Affordable

Opioids •30-50% pain reduction•

Effective in more severe pain

•

Broad and significant effect on pain

•

Intolerable side effects-constipation, vomiting, respiratory depression, sedation, confusion, etc

•

Tolerance with long term use•

Addiction and diversion potential•

Controlled substance classification

Duloxetine •

30-50% pain reduction•

Effective in moderate to severe patients

•

Effective across multiple Chronic conditions: DPNP, FM, LBP and OA•

Neuropathic

and Inflammatory conditions

•

No TCA-like side effects• Nausea

•

Effective in MDD and GAD•

Not effective for sleep (non-sedative)

36

3748th Annual Meeting of the EASD, Berlin October 02, 2012

Efficacy of

Duloxetine

and

Pregabalin Indirect comparison in patients with painful diabetic neuropathy

Comparable clinical efficacy

Duloxetine Pregabalin

Quilici

S et al. BMC

Neurol 

2009 Feb 10;9:6.

►

The Combo-DN study primarily investigated the combination of

duloxetine

(DLX) and

pregabalin

(PGB) in patients with DPNP not responding to standard doses of each drug (primary objective).

►

The study also included for the first time, a randomised, double-

blind, parallel-group comparison of DLX and PGB for initial pain therapy (important secondary objective).

Brief Pain Inventory Modified Short Form 24‐hour Average Pain at Week

8 of the Initial Treatment Period  – Categorical Analysis

38

Note: p-values from Fisher's exact test for the between-treatment difference

.

Initial Treatment Duloxetine

(60 mg/day) vs.

Pregabalin

(300 mg/day)

48th Annual Meeting of the EASD, Berlin October 02, 2012

1. Moore et al. Ann Rheum Dis 2010;69(2):374-9. 2. Moore et al. Pain 2010;149:431-4. 3. Data on File, Eli Lilly and Company.

NNT for ≥30% Pain Reduction

Naproxen1 1000 mg

Celecoxib1 200 mg

Etoricoxib1,2 30-90 mg

Duloxetine3 60-120 mg

OA 4.8 4.7 30 mg: 4.360 mg: 4.0 6.9, 11.6

CLBP - - 60 mg: 7.590 mg: 6.9 7.8, 14.1

PresenterPresentation Notes[Source: Moore RA, et al. Ann Rheum Dis 2010;69(2):374-9. Table 1; Lilly data /Home/lillyce/prd/ly248686/integrations/cpse/programs stat/tfl_output/nntnnh1].Abbreviations: OA: osteoarthritis, CLBP: chronic low back pain, NNT: Number needed to treatKey Points:Number needed to treat (NNT) with duloxetine in OA and CLBP were similar to NNTs for other pharmacotherapeutic interventions.For duloxetine, NNTs are shown for OA-1 (Study HMFG) and OA-2 (Study HMEP), and for CLBP-1 (Study HMEN) and CLBP-3 (Study HMGC)NNT is an alternative method to express response rates observed in placebo-controlled clinical trials. NNTs are typically used for meta-analysis, with the goal to make an indirect comparison of efficacy across multiple similarly designed clinical trials.References:Moore RA, Moore OA, Derry S, Peloso PM, Gammaitoni AR, Wang H. Responder analysis for pain relief and numbers needed to treat in a meta-analysis of etoricoxib osteoarthritis trials: bridging a gap between clinical trials and clinical practice. Ann Rheum Dis 2010;69(2):374-9. Moore RA, Straube S, Derry S, McQuay HJ. Chronic low back pain analgesic studies--a methodological minefield. Pain 2010;149(3):431-4. Data on file, Eli Lilly and Company. Lilly data /Home/lillyce/prd/ly248686/integrations/cpse/programs_stat/tfl_output/nntnnh1

Pooled

fibromyalgia

Studies 1‐4Mease et al. Pain Manage 2011;1(2):159-70.

TEAEs

with Rate of ≥5% and 2x Placebo

% o

f Pat

ient

s

PresenterPresentation NotesCymb00054970Study Codes: Study 1: HMBO, Study 2: HMCA, Study 3: HMCJ, Study 4: HMEF[Source: Mease PJ et al. Pain Manage 2011;1(2):159-70. Pg 167, Table 4.]Abbreviation: TEAE: treatment-emergent adverse event

Key Points:Nausea and dry mouth are among the most common treatment-emergent adverse events in patients with fibromyalgia that are treated with duloxetine.Duloxetine’s TEAE profile in fibromyalgia was similar to that seen in other indications.

Reference:Mease PJ, Walker DJ, Alaka K. Evaluation of duloxetine for chronic pain conditions. Pain Manage 2011;1(2):159-170.

+ Millions of people suffer from chronic pain  every day

– Osteoarthritis

(OA) pain and chronic low back pain  (CLBP) are two of the most prevalent causes

– Novel approaches for the management of pain are  needed

+ Duloxetine

provides a clinically relevant  analgesic effect for OA, CLBP

+ Duloxetine

is safe and well‐tolerated

PresenterPresentation NotesAbbreviations: MDD: major depressive disorder, DPNP: Diabetic peripheral neuropathic pain, GAD: generalized anxiety disorder, FM: fibromyalgia

+ Physical exercise1.

Walking, running, aerobic exercise, cycling ‐reduces 

pain and improves function for OA and

fibromyalgia2.

Stretching and strengthening –improve pain and 

function in chronic low back pain+ Physical therapy1.

Manipulation and massage –effective for LBP

2.

Traction and spinal manipulation ‐? Benefit3.

TENS –adjuvant role for localized pain

+ Intervention based on learning and cognitive  change

+ Effective in variety of chronic pain conditions – chronic LBP,

fibromyalgia, OA and RA

+

Best result with physical exercise as part of a multimodal

treatment program –cornerstone 

of the treatment for chronic widespread painBergman. Best

PracRes

ClinRheu2007;21:153‐166

+ Improvement in pain and joint function in OA  knee

Witt. Lancet 2005;366(9480):136‐143

+ Short term effect in chronic low back painFurlan(Cochrane Collabo). Spine 2005;30(8):944‐63

+ Beneficial as an adjuvant therapy

+

Careful assessment with emphasize on pain  management could improve the management 

of pain in primary setting.+

Use of multi‐modal interventions: drugs and 

non‐pharmacological interventions is more  successful

+

Potentiation

of 5‐HT and NE activity in the CNS with duloxetine

is shown to result in superior pain 

inhibition and better outcome of pain control

Thank you!

Questions…

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