Innovations in the Relief of Pain and Suffering

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Innovations in the Relief of Pain and Suffering

• A review of the newest methods to provide symptom
  relief for critically ill children

Gary Allegretta, MDMedical Director, The Jason
Program E-mail medicaldirector_at_jasonprogram.orgW
eb www.jasonprogram.org -- October 2002
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Outline

• Fundamental Physiology of Pain
• Creative Applications of Science
• Neuropathic Pain NMDA Magic
• Bone Pain
• Complimentary Therapies
• Non-Pain Syndromes
• Myoclonus
• Nebulized Everything

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Pain Physiology

• What is Pain?
• The "standard" definition of pain is that of the
  International Association for the Study of Pain-
  "An unpleasant sensory or emotional experience
  associated with actual or potential tissue
  damage, or described in terms of such damage.
  Pain is always subjective.
• This definition is extremely unfortunate.
  Definitions tend to force people into particular
  ways of thinking. By concentrating on the
  subjective nature of pain, this definition allows
  us to conveniently ignore individuals whose
  physical findings are all consistent with a
  diagnosis of "pain", but who cannot relate a
  subjective feeling of pain. Indeed, it tells us
  that (appearances to the contrary) such people
  are not in pain!

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Peripheral Receptors

• Nociceptors pain-specific receptors
• First Pain
• A sharp sensation, localized to a well-defined
  part of the body surface
• High-threshold mechanoreceptors
• Second (Visceral) Pain
• Stimulation of tissue receptors(none exist in
  brain)
• Dull, aching, poorly localized, persistent,
  sometimes referred to body surface
• Polymodal receptors

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Mediators of Pain

• Neurotransmitters
• Substance P (sP), Vasoactive Intestinal
  Polypeptide (VIP), Calcitonin gene-related
  peptide
• Others
• Prostaglandins, histamine, serotonin, ATP, K, H
  ions

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Neural Pathways
Afferent Stimuli Large myelinated A ? fibres
1st Pain Small myelinated A ? fibres
2nd PainLarge non-myelinated C fibres
The gate theory
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Wind-Up
NMDA activation neuron ? activity

• Abnormal temporal summation of 2nd pain
• Allodynia
• Hyperpathia

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Opioid Receptors Inhibition

• Opioid receptors inhibit transmission of pain
  signals (pre-synaptically)
• Types mu (?), kappa (?), delta (?)
• CNS Effects
• Analgesia, dysphoria, drowsiness,respiratory
  depression, antitussive, inhibits release of ACTH
  and gonadotropins, increases the release of ADH,
  miosis, stimulates CTZ, then depresses this
  vomiting center
• Other Effects
• Vasodilatation, constipation, smooth muscle
  spasm,tolerance and dependence

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Inhibition at the Dorsal Cord

• Local connections control gating
• Painful stimuli arriving on C fibres are modified
  by A? and A? fibres, closing the gate on
  further incoming pain signals
• Pharmacology is complex
• Stimulation of opioid receptors blocks sP
  release Post-synaptic effect also
• GABA, somatostatin, neurotensin, CCK,
  neuropeptide Y all play a role
• Intrathecal opioids octreotide are effective

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NMDA Receptors

• With active pain, prolonged firing of C-fiber
  nociceptors causes release of glutamate which
  acts on N-methyl-D-aspartate (NMDA) receptors in
  the spinal cord.
• Activation of NMDA receptors causes the spinal
  cord neuron to become more responsive to all of
  its inputs.
• NMDA-receptor activation increases the cell's
  response to pain stimuli, and decreases neuronal
  sensitivity to opioid receptor agonists.
• NMDA-receptor antagonists, such as
  dextromethorphan, can suppress central
  sensitization in experimental animals.
  Administration of NMDA-receptor antagonists with
  an opioid may alleviate pain and prevent
  tolerance to opioid analgesia.

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Ascending PathwaysPET Imaging During Pain
Experience
Thalamus
Basal Ganglia
Cingulate Gyrus Sensory Cortex
Thalamus
Cerebellum
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Descending Pathways

• Origin of pain modulation
• Cortex, thalamus, brainstem (PAG)
• Serotonin, opioids, GABA inhibit pain
• Separate nor-adrenaline inhibition
• TCAs (inhibit NOR re-uptake) effective here

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Review

• Fundamental Physiology of Pain
• Creative Applications of Science
• Neuropathic Pain NMDA Magic
• Bone Pain
• Complimentary Therapies
• Non-Pain Syndromes
• Myoclonus
• Nebulized Everything

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Creative Application of Science

• Neuropathic Pain
• Associated with greater resistance to opioids
  than other pain syndromes
• Higher opioid doses have been effective
• ? Amenable to inhibition of pain signals
• NMDA Magic

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Opioids Neuropathic Pain

• Tramadol
• Centrally acting analgesic opioid serotonin
• Two studies, benefit _at_ 200 - 300 mg BID
• Oxycontin
• 1 study in post-herpetic neuralgia, benefit
• IV Fentanyl
• Anecdotal benefit
• Methadone
• Controversial
• Benefits in pain, paresthesias, allodynia

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NMDA Magic

• Blocking NMDA receptors inhibits pain
• Particularly Effective with Neuropathic Pain
• The problem -
• Complete blockade causes memory impairment,
  ataxia, psychomimetic events, and incoordination
  (PCP site)
• The research -
• Develop antagonists that block the pathologic
  NMDA actions but allow the physiologic ones

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NMDA Neuropathic Pain

• Dextromethorphan /- Morphine
• DM is a low-affinity NMDA antagonist
• Doses 400 mg/day benefit in diabetic
  neuropathy
• Standard dose is about 1 mg/kg
• Rats DM MSO4 prevented tolerance dependence,
  increased peak analgesia duration, no ? adverse
  effects
• People 2 studies showed 11 DM MSO4 ? good
  pain relief with less MSO4
• Long-term tolerability mild nausea, vomiting,
  somnolence, constipation, confusion, pruritis,
  headache

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NMDA Neuropathic Pain

• Ketamine
• Effective in sub-anaesthestic doses for
  refractory neuropathic pain
• Synergistic with narcotics
• Reverses wind-up (unlike morphine) and reduces
  area of hyperalgesia

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NMDA Neuropathic Pain

• 12 yr.-old girl, severe neuropathic pain50
• Cervical GBM
• Pain allodynia (gentle hugspain) in all
  dermatomes below the tumor
• Morphine ineffective
• Ketamine, 7.5 -10 mg IV bolus ? CI
• Added prophylactic benzodiazepenes
• Transferred to home, 250 miles away
• Remained awake pain-free

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NMDA Neuropathic Pain

• ?2-Adrenergic Agonists (adults)
• Inhibit pain transmission in spinal cord
• Oral 40 pts. with post-herpetic neuralgia
  preferred clonidine, 200 mcg vs. codeine 120 mg
  vs. ibuprofen 800 vs. placebo
• Epidural
• CL 150 mcg MSO4 5 mg (dbl blind,
  arachnoiditis)
• CL opioids in deafferentiation pain (series of
  studies)
• CL epidural MSO4 benefit in 56 vs. 5 with
  MSO4
• Topical
• Effective in postherpetic neuralgia diabetic
  neuropathy

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NMDA Neuropathic Pain

• Clonidine - children
• Ointment
• 9 yr-old with zoster post BMT47
• clonidine ointment was thought to be effective
• We conclude that clonidine can be administered
  to children without causing side effects.
• Intrathecal/Subarachnoid
• For paediatric circumcision, under general
  anaesthesia, the addition of clonidine 2 mcg x
  kg(-1) to low volume (0.5 ml x kg(-1)) caudal
  anaesthetics has a limited clinical benefit for
  children undergoing circumcision.48

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NMDA Neuropathic Pain

• Clonidine
• Oral or transdermal
• a useful antineuropathic agent49
• Commonly used empirically
• PO Dose 2-4 mcg/kg/day, given Q 4-6 hrs
• Transdermal patch 0.1-mg/day
• ? Inversine (less sedating than clonidine)

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NMDA Neuropathic Pain

• Lidocaine
• Useful diabetic neuropathy, zoster
• Not useful ischemic pain allodynia neuropathic
  cancer pain
• New idea Lidocaine Patch
• Post-herpetic neuralgia --5 lidocaine in patch
  form applied to allodynic skin for 12 hours is
  effective without systemic adverse effects

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NMDA Neuropathic Pain

• Methadone42 (see handouts), 43, 44
• Racemic
• R isomer ? agonist, NMDA antagonist
• S isomer NMDA antagonist, 5-HT nor-epi
  reuptake block
• Additive analgesia, limited tolerance
• More effective than MSO4 for chronic use
• Terminal T 1/2 up to 190 hours
• efficacy for neuropathic pain syndromes is
  largely anecdotal.
• (but occasionally impressive)44

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Biphosphonates for Pain Rx

• Mechanism53
• Inhibit osteoclasts
• Reduce rate of bone turnover
• Uses
• Osteoporosis prevention
• Rx bone pain
• Rx RSD
• Rx osteogenesis imperfecta

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Efficacy in Rx Bone Pain

• Cochrane database review54 (1966-1999)
• 30 randomized studies, 3682 pts.
• Few studies with available data
• Benefits for pain relief
• NNT _at_ 4 weeks 11 (6-36)
• NNT _at_ 12 weeks 7 (5-12)
• Nausea vomiting frequent, not sig. to Rx
• Conclusions
• not first line therapy
• more studies are needed

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Histiocytosis Case Reports

• 14 yr-old boy with histiocytosis (LCH)55
• multifocal bone pain not responsive to chemo,
  steroids, NSAIDS, narcotics
• Rx pamidronate IV, 90mg QD X 3 days
• Responded well to 2 cycles
• Deterioration responded to retreatment

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Histiocytosis Case Reports

• 23 yr-old woman with LCH57
• Dx. Age 10 (hip lesion) DI at 15 chemo at 19
• Severe iliac shoulder pain X 3 mos. Lesions in
  skull and femoral head as well. pain 9/10
• Partial relief with MS Contin, 60 mg BID
• IV pamidronate, 90 mg?pain 6 after first
  infusion pain 2 after 4 infusions
• MSO4 stopped

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Pamidronate for RSD

• 39 yr-old woman, throughout pregnancy56
• RSD both lower legs could not walk
• Pain worse after delivery
• Bone density diffusely low
• Wanted to nurse her infant
• Pamidronate, IV monthly
• Rapid decrease of pain resolved at 6 mos
• No pamidronate in breast milk
• Infant healthy

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Review

• Fundamental Physiology of Pain
• Creative Applications of Science
• Neuropathic Pain NMDA Magic
• Bone Pain
• Complimentary Therapies
• Non-Pain Syndromes
• Myoclonus
• Nebulized Everything

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Complimentary Therapies

• Cognitive Behavioral Approaches
• Breathing Techniques
• Guided Imagery
• Progressive Muscle Relaxation
• Biofeedback
• Hypnosis
• Devices
• TENS
• Acupuncture
• ShotBlocker

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Education

• Simple preoperative information about surgery
  and what to expect is a good first step to
  decrease postoperative pain.1
• Toddlers after hernia surgery
• Lower pain scores in the education group
• Teach ages

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Distraction

• Toddlers
• Blowing bubbles, playing with pop-ups, looking
  through kaleidoscope2
• Preschoolers
• Imagine a superhero turning of the pain switch3
• 6 yrs. engage well in abstract interventions
  (guided imagery, counting, breathing techniques)

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Suggestion

• The Magic Glove Technique4
• Imaginary glove (or blanket, for large areas) is
  slowly placed where a procedure is to be
  performed. The glove lessens the pain.
• Requires patient
• Willingness
• Trust in the coach
• Strength Energy to participate
• Combination with meds effective in children with
  leukemia5

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Breathing Techniques

• Can enhance relaxation distraction3
• Two types
• Rhythmic, deep-chest
• Best for older children
• Push the pain out
• Patterned, shallow
• Best for younger children
• Use with images (e.g. mimic a train -
  toot-toot)
• Sense of mastery replaces helplessness6

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Guided Imagery

• Relaxed, focused concentration
• Guided imagery tapes useful in Milwaukee
• Documented responses ? O2 consumption,BP, HR,
  muscle tension, serum lactate7

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Progressive Muscle Relaxation

• Introduced by Jacobsen8 in early 1970s
• Extensive practice with systematic muscle tensing
  releasing
• Technique -
• Tense a muscle for 10 seconds, release, compare
  tense vs. relaxed feelings
• Differentiate painful stimuli
• Anxious people relax deeply
• Can be applied to children

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Biofeedback

• Instruments amplify physical states
• EEG, electro-myography, skin temperature,
  temporal pulse feedback
• Effects muscle relaxation, peripheral cranial
  blood flow9
• Requires skilled trainers, specialized equipment,
  and frequent practice
• Most useful for chronic pain

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Hypnosis

• Altered state of consciousness - focused
  concentration
• Effective with chronic behavioral issues10
• Typically performed by psychologists
• Efficacy validated in surgeries11,12 and invasive
  procedures13,14
• No Fears, No Tears15
• www.hypnosis.com
• www.drshields.com

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Pain Inhibition Devices

• Acupuncture
• Low frequency, high amplitude stimulation of
  small A? fibres
• Transcutaneous Electrical Nerve Stimulation
  (TENS)
• High frequency, low amplitude large fibre
  stimulation
• Cranial Electric Stimulation
• Skin rubbing and ?? ShotBlocker

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Acupuncture

• Used in China for 5000 years
• Theory --
• Energy (Chi) flows through the body along
  channels (meridians), connected by acupuncture
  points.16 Pain obstructed chi, and restoring
  flow reduces the pain.
• Gained respect in western medicine after reporter
  traveling with president Nixon received
  acupuncture as pain relief after an appendectomy.
  NIH then sponsored physician visits to China.

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Tools of the Trade
Patient Cooperation Required
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Acupuncture Data

• Promising results in tennis elbow, nausea,
  dental pain, fibromyalgia, back pain, menstrual
  cramps, headache, stroke rehab.17
• Postoperative18 and chemotherapy induced
  nausea.19
• Children --
• Stress response of premature infants undergoing
  retinoscopy for ROP. Lower salivary cortisol
  levels in group receiving acupuncture.20

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The Boston Experience23

• Retrospective, 47 pts with chronic pain
• 79 female, 96 white, median age 16 yr.
• DX migraine (7), endometriosis (6), RSD (5)
• Median of 8 treatments over 3 months
• Insurance coverage for 15
• RX needles (86), heat (85), magnets (26),
  cupping (26)

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Results

• Initial reaction to referral -
• pleased (10/42)
• willing to try, open, skeptical, afraid
• Experience rating (pt. ? parent) -
• positive or pleasant (65)
• negative or unpleasant (10)
• neutral, strange (10)
• Helpfulness (? )
• yes (65), no change (30), worse (0.5), unsure (4)

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NIH Consensus Statement21
The introduction of acupuncture into the choice
of treatment modalities that are readily
available to the public is in its early stages.
Issues of training, licensure, and reimbursement
remain to be clarified. There is sufficient
evidence, however, of acupuncture's value to
expand its use into conventional medicine and to
encourage further studies of its physiology and
clinical value.
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Aetna Coverage Policy22
Aetna covers acupuncture when it is used in a
lieu of other anesthesia for a surgical or dental
procedure covered under the health benefits plan,
and the health care provider administering it is
a legally qualified physician practicing within
the scope of his/her license.
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TENS

• Transcutaneous Electrical Nerve Stimulation
• Theories of Action
• Gate-Control
• Endorphin Production
• Efficacy proven in post-surgical pain
• Opinions differ regarding settings
• Vary frequency and strength of the signal

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Tens Unit
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Tens Placement
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Cranial Electrical Stimulation24
The Use of Cranial Electrotherapy Stimulation in
the Management of Chronic Pain A
Review NeuroRehabilitation, 14 (2000) 85-94
CES is the application of a small amount of
current, usually less than 1 milliampere, through
the head via ear clip electrodes.It had been
developed in the U.S.S.R. in 1954,and by the
late 1960s it was being researched in both animal
and human subjects at several US university
medical schools.
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Patient-Reported Results
54
Chronic Spinal Pain
55
The treatment of fibromyalgia with cranial
electrotherapy stimulation.
----- Journal of Clinical Rheumatology,
7(2)72-78, 2001.
Fibromyalgia
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Psychological Effects
57
CES Biofeedback for Migraines
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ShotBlocker

• Thin plastic device designed to reduce the pain
  of minor injections

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Use of the ShotBlocker
In my office, using the ShotBlocker on over 100
patients, ages ranging from 4-18 years, I have
noticed a significant reduction in the perceived
pain from my patients receiving minor injections
and immunizations. Although anecdotal, the
response has been striking. -- James Hunter,
MD, PhD
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Scientific Results
Ordering Information Bionix Medical
Technologies Phone [phone]Fax
800-455-5678Web www.bionix.com Pricing 25 per
box . 23.75100 per box
85.00
61
From Complimentary Therapies for Acute Pain
Management -Rusy Weissman1
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Review

• Fundamental Physiology of Pain
• Creative Applications of Science
• Neuropathic Pain NMDA Magic
• Bone Pain
• Complimentary Therapies
• Non-Pain Syndromes
• Myoclonus
• Nebulized Everything

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Non-Pain Syndromes

• Myoclonus
• Nebulized Everything
• Guaifenesin
• Opioids for Dyspnea
• Lidocaine for cough hiccups

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Myoclonus

• Melatonin in treatment of non-epileptic myoclonus
  in children
• Developmental Medicine Child Neurology 1999,
  41 255-259
• Melatonin - pineal hormone regulates sleep
• Absence ? seizures MLT is anticonvulsant
• 1.25µ/kg IV MLT causes EEG slowing and sleep
• Half-life
• Case Reports
• Three children with severe sleep disorders due to
  myoclonus
• 1 had epilepsy, 2 without epilepsy

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Case I

• 15 month-old boy with holoprosencephaly spastic
  quadriplegia no epilepsy
• Prolonged clusters of myoclonus only before sleep
• Lasted several hours ? crying and exhaustion
• No change in sensorium
• Benzodiazepenes failed
• 5 years of age2.5 mg oral FR MLT QHS
• Myoclonus stopped after 2 days returned if MLT
  stopped
• 8 years of age developed AM myoclonus 4mg CR
  MLT (replacing 5mg FR MLT) successful

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Case II

• 5 year-old neurologically normal girl developed
  brief myoclonus at 6 weeks of age
• Myoclonus appeared in drowsiness continued
  during sleep
• EEG normal in all states
• Increasing sleep fragmentation
• 2 years of age 5 mg FR MLT began
• Myoclonus subsided within 2 days returned if MLT
  stopped
• 5 years of age
• remains neurologically normal
• changed to CR MLT
• no adverse effects noted

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Case III

• 9 year-old girl diagnosed with mitochondrial
  encephalopathy ? MR, CP, epilepsy
• Several years of recurrent pre-sleep myoclonus
• No response to various anticonvulsants
• Gradual worsening of EEG since 5 months of age
• 3 years of age MLT 3 mg QHS started
• Myoclonus stopped within 2 days
• 9 years of age
• EEG improved
• No myoclonus
• No adverse effects

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Nebulized Everything

• Guaifenesin (glycerol guaiacolate)
• The idea If the cough reflex is strong, loosen
  secretions with nebulized saline and
  guaifenesin.26
• Opioids for Dyspnea
• Lidocaine for cough hiccoughs

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Managing secretions25

• Saliva
• produced in the oral cavity
• under neurologic control
• 3 pints/day
• Sputum
• mucous secretion produced by pulmonary epithelium
• bronchorrhea is 100 ml/day production

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Improve Mucociliary Clearance

• Guaifenesin - creosote derivative
• ? amount of upper airway fluid25
• ? fluid surface tension adhesiveness25
• ?except in chronic bronchitis34
• efficacy enhanced by strong cough25
• Safety
• 100 mg/kg horse anesthesia
• 150 mg/kg pig EEG changes of sedation
• No side effects in chronic bronchitis _at_ 1600
  mg/D34
• Our experience

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Opioids for Dyspnea

• Pharmacology
• The individual relative bioavailabilities of
  inhaled morphine varied from 9 to 35, with a
  mean of 17.28 (50mg neb, 10mg po, 5 mg IV)
• The systemic bioavailabilities of morphine
  were5 /- 3 and 24 /- 13 for the nebulized
  and oral routes respectively. 29(50mg neb, 10mg
  po, 5 mg IV)
• Peak plasma morphine concentrations were
  achieved more rapidly after nebulized than oral
  morphine, occurring within 10 min in all
  subjects. 29

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Efficacy

• Pediatrics. 2002 Sep110(3)e38.
• 20-kg boy with end stage cystic fibrosis
• Dose 2.5 ? 12.5mg (0.125-0.625 mg/kg)
• Venous pCO2 ?
• Conclusions
• a mild, beneficial effect on dyspnea, with
  minimal differences found between the lowest and
  highest doses.
• More studies are needed to determine what, if
  any, the optimum dose of nebulized morphine is
  for children.

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Efficacy

• Selected Reports - Adults
• Our preliminary data confirmed the possible
  clinical benefit for dyspneic patients.31
• 20 mg (0.3 mg/kg) MSO4 in 5 ml NS
• 8 of 15 pts. had less dyspnea without adverse
  effects.
• We conclude that the subjects benefited from
  saline or morphine via a placebo effect and/or a
  nonspecific effect, and that nebulized morphine
  had no specific effect on dyspnoea.33
• Doses of 10 or 20mg
• Studies that administer single predetermined
  doses that are not titrated to relief may report
  false-negative results.32

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Efficacy

• These case studies serve to indicate that
  nebulized opioids may be a very beneficial and
  effective alternative to the oral and
  subcutaneous routes in patients with terminal
  cancer.35
• Topicnebulized morphine (3 of 5), Read 43
  timesConf.Interdisciplinary DiscussionFrom
  Angela Hall (ahall7777_at_aol.com)Date Monday, May
  03, 1999 0441 PM
• I have had TREMENDOUS success using nebulized
  morphine in respiratory distress. I have had
  patients who could respond verbally and those who
  could not. I also have used this medication on
  two ventilator patients with GREAT results. Not
  only does it relax the smooth muscle but it also
  decreases the anxiety and air hunger. I would be
  happy to discuss it further if you have any
  questions.EPERC Discussions

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Nebulized Lidocaine

• Pediatric Safety36
• 6 severely asthmatic patients followed in the
  Pediatric Allergy and Immunology Section, Mayo
  Clinic, 1996
• Dose 0.8 mg/kg/dose to 2.5 mg/kg/dose TID-QID
• Mean duration of therapy 11.2 mos (7-16 mos)
• Toxicity None
• lidocaine may prove to be the first non-toxic,
  steroid alternative to patients with severe
  steroid-dependent asthma.

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Pediatric Safety

• New York Medical College37, 1997
• In flexible bronchoscopy -
• 20 pts., not intubated, no cardiac or hepatic
  disease
• Dose 8 mg/kg or 4 mg/kg of nebulized 2
  lidocaine by face mask prior to bronchoscopy
  (randomized)
• Safety serum lidocaine levels much
• Conclusion Nebulized lidocaine in doses up to 8
  mg/kg appears to be safe and moderately effective
  as a topical anesthetic for flexible bronchoscopy
  in infants and children.

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Efficacy

• Hiccups38
• 58 yr.-old man, 5 mos. Hiccups
• Dose 3ml, 4 topical lidocaine, QD X 3 D
• Resolved for 3 weeks, retreated successfully
• Cough39,40
• Type Intractable, Habit
• Dx. Asthma, COPD
• Efficacy Very effective
• Breathlessness41 (terminal care in adults)
• Ineffective
• Asthma36
• Promising in adults and children

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Protocol Variations

• Bronchodilator pre-treatment
• lidocaine can cause bronchospasm
• Cardiac monitoring
• lidocaine arrthymias
• /- 1.0 ml 0.5 bupivicaine
• NPO for 1-several hours after Rx
• Loss of gag reflex

79
Take-Home Reminders

• Research into the physiology of pain perception,
  especially the NMDA receptor, may lead to more
  effective treatments with less adverse effects.
• Creative application of medications not initially
  intended for pain relief, such as the
  bisphosphonates, may also yield effective pain
  treatments.

80
Take-Home Reminders

• Complimentary interventions are now effective,
  safe treatment options, even though we may not
  understand their mechanisms of action well.
• Melatonin is useful in decreasing myoclonus in
  children.
• You can put anything into a nebulizer, and some
  may actually help your patient.

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Thanks for listening