An Introduction to the Management of Chronic Noncancer Pain...

Dr. Jeff Ennis September 17, 2007 1

An Introduction to the Management of Chronic Noncancer Pain and …..


How to Build a Boat


Qualifications


Agenda

Definition of chronic painBurden of IllnessAnatomy of painDiagnostic ConsiderationsTreatment

PharmacologicNon-Pharmacologic


Those who do not feel pain seldom think it is felt.

Samuel Johnson


The Pain Experience

Acute Chronic Cancer

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Operational Definition of Pain

“Pain is whatever the experiencing person says it is, existing whenever he says it does.”

McCaffery and Pasero: Pain: Clinical Manual, 1999.



Types of Pain



Psychogenic Pain

“The term ‘psychogenic pain’ has been used to define pain that is believed to be caused by or primarily influenced by a psychopathological process. The use of this term is discouraged because it lacks precision and has the potential to stigmatize patients when applied inappropriately. True primary psychological pain disorders are rare” …. Canadian Pain Society

It is a term often applied to a patient who has pain, that is difficult to diagnose, difficult to treat, difficult to discharge and difficult to like…..Ennis



IASP Definition of Pain

An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.


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Why Feel Acute Pain?It is an important alarm system that warns us of threatened or ongoing tissue damage.

It is designed to protect us.

You cannot survive without it.

All organisms appear to move away from ‘noxious’ stimuli.


The Burden of Illness-Canada

29 % of respondents reported chronic noncancer pain.

Average pain duration was 10.7 years

Average intensity was 6.3 on a scale of 1-10 (10 being the worst pain ever experienced)

Almost half were unable to attend social/family events

Mean number of days absent from work in the past year due to chronic pain was 9.3

Moulin D, et. al., Chronic Pain In Canada-Prevalence, treatment, impact and the role of Opioid Analgesia. Pain Research and Management. 2002, 7(4): 179-184. (defined chronic pain as past 6 months)

http://primuul.com/~kirk/content/art/burden.jpg


Burden of Illness-Canada

In pain clinic samples, the rate of co-morbid major depression ranges from 30-45%

In the community:

WHO Collaborative Study on psychological problems in primary care found 32% of patients with a ‘somatoform pain disorder’ met criteria for a mood disorder

Canadian Survey found presence of depression in 5.9 % of the ‘pain free’ study population and present in 19.8% of surveyed individuals with chronic low back pain.

Currie & Wang, Chronic Back Pain and Major Depression in the General Canadian Population. Pain, 107: 54-60.




Burden of IllnessThere is a high co-morbidity of mood disorder in patients with chronic pain

Physical Symptoms are common in patients with affective disorders

The presence of a mood disorder is associated with an increased risk for developing chronic musculoskeletal conditions.

Sullivan MJ et al: Pain 1992, 50:5-13, Von Korff L, et. al: Pain. 1993; 55:251-258, Magni et. al: Pain. 1994; 56:289-297



Burden of IllnessCo-morbid mood disorders increases risk of poor outcome in patients with chronic non-cancer pain (CNCP).

Increased pain behaviorsGreater pain intensity, less life control, more passive coping techniquesPoor surgical outcome (back surgery)Poor outcome in RA, and low back pain

Weickgenant.Pain. 1993, 53: 95-103, Junge et. al. Spine. 1995; 20:460-468, , Katz & Yelin J Rheumatol . 1993; 20: 790-6



Anatomy of Pain


The Spinothalamic Tract



Pain Mood Connection



Normal Pain PathwaysThis is a complex antinociceptive (perception of pain) system.

Pain signals release endorphins in the periaqueductal Gray Matter and enkephalins are released in the nucleus raphe magnus of the brainstem.

Endorphins bind to mu-receptors on presynaptic terminals of nociceptors and postsynaptic surfaces of dorsal horn neurons. Enkephalins bind delta opioid receptors on inhibatory interneurons in the substantia gelatinosa of the dorsal horn. This leads to the release of GABA in order to dampen pain.Spinal interneurons release dynorphins which activate kappa receptors leading to closure of N type calcium channels in spinal cord cells that relay pain to the brain.

Other molecules are released following enkephalin release (norepinephrine, oxytocin, relaxin) which inhibit pain transmission.

This pain inhibiting system serves to allow us to function after minor injury. P

Problems arise from disorders of the pain sensing and pain relieving systems. One example of a pain relieving problem might be ‘fibromyalgia’.


Anatomy of Pain


Pain Mood Connection (Limbic Structures)



Anatomy of the Limbic System: Cingulate Gyrus


Functional Neuroanatomy of Pain

Nociceptive Input

Nociceptive Sensations

Perceived Intrusions or Threat

Immediate Pain Unpleasantness

Second Order Appraisal Secondary Pain Affect

Autonomic arousal

S1,S2,PCC

PPC, IC

ACC

RF, HYP, SMA, AMYG

PFC

S1 = primary sensory cortex

S2 = secondary sensory cortex

PCC= posterior cingulate cortex

PPC= posterior parietal complex

IC = insular cortex

ACC= anterior cingulate cortex

PFC= Prefrontal cortex

RF = reticular formation

HYP = hypothalmus

SMA = supplementary motor areas

AMYG=amygdala

http://www.portfolio.mvm.ed.ac.uk/studentwebs/session2/group10/bestbrain.jpg


The Two Components of Pain

2 neuranatomical connections of pain:

1 a sensory-discriminative dimension that identifiesits intensity, quality, and spatiotemporal characteristics

The sensory component of pain

2 affective-motivational dimension that processesits negative valence and unpleasantness

The emotional component of pain


Pain-Induced Activation of the Brain

Sensitive Less Sensitive

Activation of somatosenory cortex, anterior cingulate cortex and prefrontal cortex are greater in sensitive subjects. Activity in the thalamus is the same.

Coghill RC, McHaffie JG, and Yen Y. Neural correlates of inter-individual differences in the subjective experience of pain. Proc. Nat. Acad Sci.


Functional Imaging and Pain

A. Vania Apkarian, Yamaya Sosa, Sreepadma Sonty, Robert M. Levy, R. Norman Harden, Todd B. Parrish, and Darren R. GitelmanChronic Back Pain Is Associated with Decreased Prefrontal and Thalamic Gray Matter DensityJ. Neurosci., Nov 2004; 24: 10410 - 10415 ; doi:10.1523/JNEUROSCI.2541-04.2004


Summary of Imaging (PET & fMRI)

In healthy volunteers, pain is associated with increased activity in the thalamus, ACC, and the somatosensory cortex

in post-external insult chronic pain, there is evidence of altered perfusion and chemical composition of the thalamus and cortex. One finding that has been duplicated is reduced resting activity in the thalamus

Some evidence suggests reduced perfusion of the thalamus in chronic pain without a history of external insult

Response to experimental pain is different between subjects with CNCP and healthy volunteers. Some evidence of widespread response of the CNS to painful insult in subjects with CNCP compared to healthy volunteers.

Pridmore et. al., The Brain and Chronic Pain. German J. Psychiatry. 2003, 6: 8-15

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Chronic Pain PathwaysIt is not just acute pain that lasts for a long time. It is not simply pain greater than 6 months.

As pain signals continue there are:

chemical changes making pathways hypersensitive to pain signals and resistant to antinociceptive input

Signals become ‘embedded’ in the spinal cord-a painful memory


Chronic Pain Pathways (glutamate)

Glutamate is the primary neurotransmitter used by nociceptors with synapses in the dorsal horn.

This binds to AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic-acid) receptors in afferent nerve ends

In chronic pain NMDA (N-methy-D-aspartate) receptors are activated but only when there is a persistent and large-scale release of glutamate. (this occurs by the dislodging of Mg ionsthat act as stoppers in the transmembrane Na and Ca channels of the NMDA receptor complex by continuously activated AMPA receptors) . This marks the transition from acute to chronic pain.


Chronic Pain Pathways (NMDA)

Activation of NMDA receptors leads to spinal neurons requiring less peripheral input to be activated. Less glutamate is required and more antinociceptive input is required to stop it.

Naturally occurring pain relievers cannot keep up with the demand and lose their effectiveness. So do prescribed opioids.

Activation of NMDA receptors causes sprouting of new connective endings in neural cells. This remodeling can lead tonew dimensions to old sensations.


Chronic Pain Pathways (consequences of Remodeling)

The emotional component of pain might increase if new connections are made to the limbic system.

Pathways to the cortex become less localized

Remodeling can also lead to the destruction and loss of cells

Remember in stroke that overstimulation of NMDA receptors from the huge release of glutamate from injured presynaptic cells leads to the burnout of adjacent postsynaptic cells. This may be occurring in the spinal cord which receives persistent pain signals.


Chronic Pain Pathways (substance P)

NMDA receptor activation leads to the release of substance P which activates Neurokinin-1 (NK-1) receptors.

NK-1 activation leads to amplification of pain signals, nerve growth and regeneration.

NK-1 activation induces production of the c-fos oncogene protein.

With persistent pain the protein spread to progressively higher levels of the cord, reaching the thalamus. In animal models itspresence has been associated with intractable pain.

This may explain why pain spreads with chronicity.


Chronic Pain Pathways (the dorsal horn reflex)

Remember that in regards to nerves afferent means to the brain and efferent means away.

In the presence of ongoing stimulation of dorsal root a ‘reflex’ is stimulated . The dorsal horn afferent releases mediators that cause nerves to fire antidromically (toward the nociceptor).

Nociceptors release chemicals locally including nerve growth factors and substance P. Substance P is also an inflammatory agent. This leads to ‘neurogenic inflammation’. Nerve growth factor increases the excitability of nociceptors. This leads to the heightening of pain signals as pain continues.

Afferent nerves may become so sensitized by persistent pain that low level stimuli leads to hyperalgesia. The pain signal might activate the typically quiescent mechanosensitive afferents in synovial tissue and viscera. With activation slight movement or deformity of tissue leads to pain.


Chronic Pain (Neuropathic Pain)

Damage to a sensory nerve leads to neuropathic pain which is insensitive to antineuropathic maneuvers.

In patients with stroke or cord injury fibers carrying touch are destroyed. If enough pain fibers regenerate they can result in pain in areas thought to be anaesthetic. This is deafferentation pain.

In tissue injury large myelinated sensory cells (A fibers) sprout terminal branches that can synapse with pain carrying fibers in the superficial layers of the dorsal horn. (touch is located deeper). This leads to allodynia which is resistant to treatment, in part because these cells do not have opioid receptors.

This might be a model for complex regional pain disorders (Reflex sympathetic dystrophy [RSD])

Damage to nociceptors can lead to opioid resistant pain because it is in the cell body that opioid receptors are manufactured and then transported to the presynaptic membrane.


The Anatomy of Chronic Pain: Summary of Findings

It is now recognized that Chronic Non-Cancer Pain results in responses in the central nervous system and peripheral nervous system that are different from those seen in acute pain.

Chronic pain should be thought of as a different diagnostic entity from acute pain and should be treated as such. It is a disease.


What is the purpose of Chronic Non-Cancer Pain (CNCP)

Nothing


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Diagnostic ConsiderationsAssess for treatable disordersLook for ‘red flags’ of serious diseaseWaddell signs indicate suffering not malingeringThink carefully as to whether another investigation is required and whyAssess for co-morbid psychiatric disorders

Major DepressionAnxiety DisordersBrain Injury (if pain is related to trauma)


Waddell Signs

Three or more signs are associated with elevations of depression hysteria and somatization on the MMPI II


Pain Behaviour, Physical Examination and the MSE


• Waddell et al. (1980) Non-organic signs”– multiple signs suggest that the patient does not have a

straight forward physical problem and that psychological factors and behavioral aspects need to be considered in your treatment approach

– not a test of credibility or “Faking”



• Patients without objective findings but with chronic pain have an increased frequency of Waddell’s signs (Vallfors,B, 1985)

• 2 or more non-organic signs + 3 or more symptoms predict a slower return to work (Fritz et al, 2000)




a. The majority of patients did not have any Waddell signs

b.The total number of Waddell signs were positively and significantly correlatedwith certain MMPI-2 clinical scales (Hy, D) and with the Beck Depression inventory.

c. In contrast to previous findings, Waddell signs were positively related to pain intensity ratings.

d.The total number of Waddell signs was positively related to perceived physicaldifficulty.

Novy, D.M. et al, Waddell Signs:Distribution Properties and Correlates.Arch Phys Med Rehabil. 1998; 79: 820-22

Waddell signs/low back pain in a Multidisciplinary Pain Program


TreatmentTreat the sensory-discriminative dimension of Pain

Treat Underlying DiseaseMedical TreatmentSurgical Treatment

Reduce PainNSAIDs*Opioids*Acetaminophen*Anticonvulsants*gabapentinoidsTCAs*


Treatment: NSAIDs

Nonspecific COX inhibitorsRisk of GI bleeds, interstitial nephritis, htn, heart failure, renal insufficiency

COX2 inhibitorsRisk of MI, CHF

Maximized acetaminophen dosing is as effective as oral NSAIDs in 40% of patients with mild to moderate OA


Acetaminophen

Over 4 gms./day can result in liver damageOverdose can lead to non-reversible damage and can be fatal


Opioids

In general, when opioid receptors are stimulated in the periphery or in the dorsal horn they inhibit the release of glutamate and prevent the transmission of pain.


The History of Opioids I

The History of Opioids has been characterized by the ongoing struggle between medical use and recreational abuse

Friedrich Sertuerner Ist isolated morphine from opium in 1803


A Brief History of Opium II

3400 BCE: Hul Gil (joy plant) is cultivated in Mesopotamia.460 BCE: Hippocrates recognizes and records the analgesic effect of opium.1527: Paracelsus dissolves opium in alcohol creating Laudanum.1606: Elizabeth I charters ships to transport opium from India to England.

1803: Friedrich Sertuerner of Paderborn, Germany isolates morphine-it is referred to as“God’s own medicine”.1841: China loses the first opium war and Britain gets Hong Kong as a spoil of war.1843: Dr. A. Wood of Edinburgh administers morphine, by injection.


1863: China loses the 2nd

Opium War and opium is legalized in China.1878: Britain passes the Opium Act (only registered Chinese opium smokers and Burmese opium eaters can use opium)1895: Bayer produces ‘heroin’

1910: Britain dismantles its opium trade1914: The Harrison Act (U.S) legalizes the use of opioids if prescribed by a physician only.1978: The U.S. and Mexican Gov’t spray poppy fields with Agent Orange. Opium importation shifts to Afghanistan. Iran & Pakistan

A Brief History of Opium III


The Opium Wars-1839 & 1860

“A Chinese effort to keep an addictive drug out of their country led to defeat and humiliation of the ancient empire at the hands of Britain and France.”

Military History. April 2003


Treatment: Meta-Analysis of Opioid Therapy II

30% reduction in pain intensity compared with placebo for musculoskeletal or neuropathic pain

Overall they are effective in the treatment of CNCP: they reduce pain and improve function when compared to placebo for both nociceptive and neuropathic pain.

Kalso et al 2004

Furlan et al 2006


Treatment: Meta-Analysis of Opioid Therapy II

Strong Opioids (eg. Morphine) were superior to naproxen (NSAID) and nortriptyline (TCA) for pain relief not function.

Only constipation and nausea were significantly more common with opioids

No good data re sexual dysfunction

No good data re abuse/addictionFurlan et al 2006


Opioid ResearchPoor or few trials investigating

Is one opioid better than another?

Management of side-effects

Opioid Rotation

‘Breakthrough’ medications

Raja et. al.. Opioids Versus Antidepressants in Postherpetic Neuralgia: an RCT. Neurology. 2002 59(7):1015-21


The Boston Collaborative Study:

Out of 11,882 patients there were 4 new cases of addiction, which is less than the general population.

Extrapolating from the cancer literature, the risk is low.

A recent review of surveys in multidisciplinary pain clinics found a range of 2-16%.

However, there is no ‘good’ data in regards to this question

Risk of Addiction


Tolerance/Dependence/

Pseudoaddiction/Abuse

http://www.chez.com/nats/images/tolerance.jpg


The role of pain and the development of tolerance is just beginning to be appreciated. Case reports have shown that patients with significant pain disorders, will go into respiratory depression if pain is dramatically reduced. There is a change in tolerance.

Tolerance


Tolerance to Morphine 1A shift to the right of the dose response curve


Tolerance to Morphine 2

High Degree of Tolerance

Moderate Degree of Tolerance

Minimal or no Tolerance

AnalgesiaEuphoria, dysphoria

SedationRespiratory Depression

AntidiuresisNausea and VomitingCough Suppression

Cardiovascular Effects

MiosisConstipation


Physical Dependence

Occurs even with low doses of opioidsWithdrawal Symptoms:

“flu-like disease”vomitingdiarrheamultiple aches and painsgoosefleshspasms

dilated pupils


Physical dependence is common.

Patients will have withdrawal when opioids are discontinued abruptly.

Patients on opioids may show subtle evidence of withdrawal between doses.

Physical Dependence


Addiction is characterized by compulsive, aberrant behaviors, focused around the acquisition and taking of a substance in spite of harm and in the case of opioids, for its unintended effects.

Pseudoaddiction is characterized by drug seeking behaviors, stimulated by poorly controlled pain. This constellation of behaviors is often mislabeled as addiction.

Addiction or Pseudoaddiction


Behaviors more characteristic of abuse

Selling prescription drugs/Prescription forgery/Obtaining prescription drugs from non-medical sources

Stealing drugs from others

Injecting oral formulations

Concurrent use of alcohol or illicit drugs

Repeated visits to other clinicians or ER w/out telling prescriber

Drug-related deterioration: work, family, social

Repeated resistance to change in therapy despite evidence of adverse drug effects.

Addiction


Behaviors Not as Suggestive of Abuse:Aggressive complaining about the need for more drugs

Drug hoarding during periods of reduced symptoms

Occasional unsanctioned dose escalation or other noncompliance

Intense expressions of anxiety/dysphoria about recurrent symptoms

Intense expression about pain

Pseudoaddiction


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Treatment: Antidepressants

TCAs outperform weak opioids in regards to functional outcomesAction thought to be related to activation of descending inhibitory tracts which are mediated by norepinephrine and serotonin. TCAs block the reuptake of these neurotransmittersThe most well studied TCA has been amitriptyline


MetaMeta--analyses (TCAs)analyses (TCAs)

Evidence for effectiveness in the treatment of headache, neuropaEvidence for effectiveness in the treatment of headache, neuropathy, central thy, central pain syndromes, atypical facial pain and postpain syndromes, atypical facial pain and post--herpetic neuralgia. herpetic neuralgia.

Recent RCT did comparison with opioids (morphine or methadone) iRecent RCT did comparison with opioids (morphine or methadone) in postn post--herpetic neuralgia (Nortriptyline or Desipramine). Both were beherpetic neuralgia (Nortriptyline or Desipramine). Both were better than tter than placebo, with trend favoring opioids that did not reach significplacebo, with trend favoring opioids that did not reach significance. ance.

Evidence for effectiveness in the treatment of soft tissue pain Evidence for effectiveness in the treatment of soft tissue pain is equivocal is equivocal (TCAs)(TCAs)

Antidepressant Therapy

Neurology. 2002. 59(7):1015-21.



In using antidepressants as analgesics-use TCAs as first line.

Nortriptyline is the major metabolite of amitriptyline and causes less sedation, constipation, urinary retention, orthostatic hypotension and falls compared to its parent molecule and has, in a number of studies, been demonstrated to be as effective as amitriptyline.

Effectiveness of TCAs has been demonstrated in the low end of therapeutic dosing for depression, but no clear guidelines for dosing are available.


Treatment: Antidepressants

Patients with CNCP are at high risk for the development of a mood disorder

The consequences of untreated mood disorder in patients with chronic pain are significant. The most serious consequence in suicide.

Antidepressant therapy can have an impact on both the sensory and affective components of CNCP

Fishbain DA: The Association of Chronic Pain and Suicide. Semin Clin Neuropsychiatry. 1999; 4:221-227



There is no compelling evidence that one antidepressant is more effective in treating depression than another. The choice of antidepressant should be based on side-effect profile and patient match, and cost.

Hansen, R.A. Annals of Internal Medicine, 2005; 143: pp 415-426.

Zimmerman, M. Journal of Clinical Psychiatry, 66: pp 603-610


Antidepressant TherapyThere is good evidence that low dose TCAs act synergistically with other antidepressants to improve their antidepressant effect.

Recommendation:

Treat the depression with an antidepressant with a good side-effect profile/patient match.

Add TCA (nortriptyline titrating to 50-75 mg) as an analgesic and to improve the antidepressant effect of the primary antidepressant.


Treatment

Treat the affective-motivational dimension of pain. Treat Suffering


Other Treatments (medications)

AnticonvulsantsFor migraineNeuropathic pain

Gabapentinoids (no impact on GABA receptors)HeadacheNeuropathic painRecent evidence for ‘fibromyalgia’

Alpha-adrenergic receptor agonists are based on the observation that these receptors inhibit pain signals

ClonidineExperimental

Conotoxins-ziconotideNMDA antagonists (ketamine, detromethoraphan, ? Methadone)


Other Treatment (non pharmacologic treatments)

Surgical Intervention when appropriateThe success of surgery depends upon patient selectionComorbid psychiatric disorders have a negative impact on outcome even if the surgery is successful

Multidisciplinary pain programsInterventional approach (anesthesia)Surgery for pain control


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Finis

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An Introduction to the Management of Chronic Noncancer Pain...

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