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HIV Pain Management: Considerations, Ideas

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Title: HIV Pain Management: Considerations, Ideas


1
HIV Pain Management Considerations, Ideas
Suggestions
  • Barry Eliot Cole, MD, MPA
  • Executive Director, American Society of Pain
    Educators

2
Where We Are in 2005
  • HIV/AIDS pandemic has not ended
  • In US approx. 1 million are HIV-infected
  • 1 in 3 HIV-infected are unaware of diagnosis
  • Major AIDS era stages pre- post-HAART
  • People being treated for HIV are now healthier,
    living otherwise normal lives
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

3
HIV and Pain Overlap
  • Neuromuscular complications are common
  • Most common pain problems are
  • Musculoskeletal
  • Distal symmetrical polyneuropathy (DIS)
  • Abdominal pain
  • Headache
  • Other neurological problems
  • Consequences of opportunistic infections
  • Glare PA. Pain in patients with HIV infection
    issues for the new millennium. European J Pain
    2001 5 (Suppl A)43-48.

4
In the Pre-HAART Era
  • Short life expectancy, so model used was that of
    cancer patients
  • Reliance upon the 3-4 step WHO ladder
  • Expectation for lots of complications
  • Glare PA. Pain in patients with HIV infection
    issues for the new millennium. European J Pain
    2001 5 (Suppl A)43-48.

5
Why Mirror Cancer Pain Therapy?
  • Was reasonable when large segments of AIDS
    patients were debilitated and considered to be
    terminal
  • Patients surveyed as late as 1998 continued to
    list pain as being associated with worse
    perceived health and perceived quality of life
  • Lorenz KA et al, Ann Intern Med 2001 134 854.

6
Post-HAART
  • Longer life with more chronicity
  • Multiple pains occur
  • Negative impact on QOL
  • More psychosocial issues
  • Use of polypharmacy common
  • Use of pyramid plus ribbon
  • Less efficacy of treatments than cancer
  • Glare PA. Pain in patients with HIV infection
    issues for the new millennium. European J Pain
    2001 5 (Suppl A)43-48.

7
What About Demanding, Complex Pain Patients?
  • Drug seekers (addicts and diverters)
  • Those with special needs
  • Minorities
  • Substance abusers
  • Multiple treatment failures
  • Personality disorders
  • Entitlement issues

8
At Risk Groups for Having Poorly Managed Pain
  • Children
  • Elderly people
  • Minorities and people of color
  • Substance users/abusers
  • Women
  • HIV()

9
Pain in the Elderly . . .
  • Daily pain is prevalent among nursing home
    residents and is often untreated, particularly
    among older and minority patients.
  • Bernabei R, et al. JAMA 1998 2791877-82

10
. . . Pain in Elderly
  • 4,003 of 13,625 (38) patients in 1492 LTCFs
    experienced daily pain due to Ca
  • 16 received NSAID or APAP
  • 32 received combo (CIII)
  • 26 received morphine (strong opioid)
  • 26 received nothing at all
  • Older patients (gt85) and minority races were less
    likely to receive analgesics
  • Bernabei R, et al. JAMA 1998 2791877-82

11
Underestimation of Pain
  • Providers concern about dependence.
  • Underutilization of analgesics occurs especially
    for opioids
  • Important to differentiate between pain from HIV
    infection or its complications and pain from
    therapy other pain syndromes occur as well
  • Breitbart W et al. Pain 1996 65 239.
  • Larue F, Fontaine A Colleau S. BMJ 1997 314
    23.

12
Pain Prevalence in HIV
  • Estimates of pain prevalence in HIV-infected
    individuals ranges from 30 to 90
  • Prevalence of pain increases as disease
    progresses
  • 30 of ambulatory HIV-infected patients in early
    stages of HIV disease experience clinically
    significant pain
  • 56 have had episodic painful syndromes of less
    clear clinical significance
  • Breitbart W, Passik SD Rosenfeld BD (1999).
    Cancer, mind spirit. Bonicas Textbook of Pain,
    4th Ed., 1065-1112.

13
All Classes of Medications Are Underutilized in
AIDS Pain
  • lt 8 of ambulatory AIDS patients reporting pain
    in the severe range received a strong opioid
  • 18 were prescribed nothing whatsoever
  • 40 were prescribed a non-opioid analgesic
  • 22 were prescribed a weak opioid analgesic
  • Only 15 received adequate therapy
  • Utilizing the Pain Management Index (PMI)
  • Under medication occurs in only 40 of cancer
    patients
  • Adjuvant analgesics were also underutilized
  • lt 10 of AIDS patients reporting pain received
    adjuvants even though 40 had neuropathic pain
  • Breitbart W, Passik SD Rosenfeld BD (1999).
    Cancer, mind spirit. Bonicas Textbook of Pain,
    4th Ed., 1065-1112.

14
Headaches
  • Common complaint from seroconversion to advanced
    HIV disease
  • Causes vary widely
  • Evaluation may require imaging study lumbar
    puncture plus good PE
  • With CD4 gt 200 little need for CT unless focal
    neurological signs, altered MSE or Sz
  • Must evaluate all worst headaches of life
  • Gifford AL Hecht FM. Headache 2001 41 441.
  • Graham CB et al. Am J Neuroradiol 2000 21 451.

15
Chronic Headaches
  • Common with HIV
  • Due to benign, non-infectious cause when early in
    HIV infection, before onset of significant
    immunocompromise
  • Masci JR (2001). Outpatient Management of HIV
    Infections, 3rd Ed., CRC Press, Boca Raton, 118.
  • Causes are muscle tension, vascular, depression,
    chronic sinusitis, antiretroviral agents
    (zidovidine) and chronic opioids
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

16
Meningitis
  • Most common cause of AIDS-related meningitis is
    Cryptococcus neoformans
  • Most infections occur when CD4 lt 200
  • Meningismus may be absent while headache fever
    are common
  • Other causes of HIV-related meningitis include
    Strepococcus pneumoniae, Haemophilis influenzae,
    Neisseria meningitidis, Listeria monocytogenes
    HSV/VZV infection tuberculosis lymphoma
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

17
Brain Lesions
  • Headaches with focal neurological abnormalities
    or seizures think SOL
  • Most common toxoplasmosis
  • Less common primary lymphoma, tuberculoma
  • Many other organisms may cause abscesses of brain
    with HIV

18
Other Headache Causes
  • Sinusitis is more common in HIV-infected than
    those without HIV
  • Bacterial, viral and fungal causes
  • Syphilitic meningitis may occur at any stage of
    infection with syphilis
  • JC virus infection causes PML
  • After LP there may be post-dural puncture
    headaches from dural leaks
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

19
Oropharyngeal Pain
  • Candida infections
  • Gingivitis and periodontitis
  • Oral ulcers
  • Neoplasms
  • Esophageal conditions
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

20
Chest Pain
  • Fairly common in HIV infection
  • If pleuritic consider bacterial pneumonia
  • Think Tb if patient exposed to Tb
  • Spontaneous pneumothorax associated with
    Pneumocystitis carinii (PCP)
  • HAART is associated with insulin resistance
    abnormal lipid metabolism
  • Coronary artery disease may occur
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

21
Back Pain
  • Most common painful condition reported
  • Singer EJ et al. Pain 1993 54 15.
  • Caused by same musculoskeletal conditions as
    uninfected people
  • IVDA may have osteomyelitis of spine with or
    without epidural abscess
  • May be due to nephrolithiasis due to indinavir
  • Policar, M Arumugam, V (in press). HIV and
    AIDS Pain, Weiners Pain Management A Practical
    Guide for Clinicians, 7th Ed., CRC Press, Boca
    Raton.

22
Abdominal Pain
  • Many etiologies involved, so workup can be
    challenging and cause unexplained potentially
  • CD4 gt 200 are unlikely to have opportunistic
    causes, but with CD4 lt 100 disseminated
    Myocobacterium avium complex (MAC) must be
    considered Cytomegalovirus (CMV) infection of
    the GI tract occurs when CD4 lt50
  • Policar, M Arumugam, V (in press). HIV and
    AIDS Pain, Weiners Pain Management A Practical
    Guide for Clinicians, 7th Ed., CRC Press, Boca
    Raton.
  • With HAART incidence of opportunistic infections
    is decreasing (69 to 13 between 1995 and 1998)
  • Monkemuller KE et al. Am J Gasteroenterol 2000
    95 457.

23
Pre-HAART Nonsurgical Causes of Abd Pain
  • CMV gastritis/enteritis/colitis 20
  • Cryptosporidium enteritis 6
  • MAC enteritis 9
  • Non-Hodgkins lymphoma 17
  • Pancreatitis 12
  • Sclerosing cholangitis 8
  • Kaposis sarcoma 5
  • Parente F et al. Scand J Gasterol 1994 29511-5.

24
Causes for Abdominal Pain
  • HIV-related
  • Iatrogenic (medication- or procedure-related)
  • Immune surveillance-related (malignancies)
  • Non-HIV-related
  • Nonspecific (resolution without specific
    diagnosis)
  • Slaven EM et al. Emerg Med Clin North Am 2003
    21 987.

25
Non-HIV-RelatedSlaven EM et al. Emerg Med Clin
North Am 2003 21 987.
  • Appendicitis
  • Peptic Ulcer Disease
  • Diverticulitis
  • Cholecystitis
  • Hepatitis
  • Alcohol-related
  • Ischemic bowel
  • Abdominal aortic aneurysm

26
Immunodeficiency-relatedSlaven EM et al. Emerg
Med Clin North Am 2003 21 987.
  • Opportunistic GI infections with MAC, CMV
    microsporidia
  • Cholecystitis (CMV)
  • Abscesses
  • Sexually transmitted disease-related
  • Proctitis

27
Immunosurveillance-relatedSlaven EM et al. Emerg
Med Clin North Am 2003 21 987.
  • Lymphomas (GI)
  • Kaposis sarcoma (KS)
  • Cancer-related obstructions
  • Other cancers/metastatic disease

28
Medication-related/iatrogenicSlaven EM et al.
Emerg Med Clin North Am 2003 21 987.
  • Perforations secondary to procedures (upper/lower
    GI tract)
  • GI upset/reflux/gastritis
  • Kidney stones (indinavir)
  • Pancreatitis

29
Enterocolitis
  • Most common GI manifestation of HIV
  • May be acute or chronic, associated with fever
    and weight loss
  • Bacteria, viruses, mycobacteria, parasites and
    fungi are causes
  • Antimicrobial therapy is indicated often with
    antimotility agents for diarrhea
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

30
Pancreatitis
  • 35-800 times more likely with HIV
  • HIV meds didanosine, Kaletra and pentamidine
    opportunistic infections with CMV, toxoplasmosis,
    mycobacteria and cryptosporidium infiltration by
    lymphoma or KS are causes
  • Elimination of offending agent (medication,
    organism) needed
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

31
Appendicitis
  • Rates of HIV infected similar to non-infected
  • Usual causes are frequent in HIV, but
    opportunistic infections may play role
  • AIDS related pathology found in 30 of cases
  • Whitney TM et al. Am J Surg 1992 164 467.
  • Commonly identified infections associated with
    appendicitis in HIV are Mycobacterium
    tuberculosis, MAC and CMV
  • Slaven EM et al. Emerg Clin North Am 2003 21
    987.
  • KS seen in cases of AIDS appendicitis
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

32
Cholecystitis
  • May occur with or without stones
  • Acalculous twice as common as cholelithiasis
  • Acalculous associated with infection with
    Cryptosporidium paarvum, Microsporidium and CMV,
    plus other pathogens.
  • Antimicrobials are warranted for infection
    surgery may be necessary in general
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

33
Cholangitis
  • Usually associated with opportunistic infections,
    malignancy or immunologic destruction of the
    biliary epithelium
  • Cryptosporidium and CMV are most common
    infections
  • Presents like cholecystitis with CD4 lt 100
  • Stents can relieve obstruction from strictures
    sphincterotomy may help treat pain along with
    celiac plexus neurolysis
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

34
Intestinal Perforation
  • Intestinal perforation in HIV infection is
    uncommon, but commonly caused by CMV related
    ulceration
  • Lymphoma, KS, histoplasmosis, peptic ulcer
    disease and appendicitis too
  • Treatment is surgery, with antimicrobials or
    chemotherapy
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

35
Other Abdominal Pain Conditions
  • Enlarged intra-abdominal lymph nodes
  • MAC, KS or TB
  • Intestinal obstruction
  • KS or lymphoma
  • Intussesception
  • Lymphoma, KS or Mycobacterial infection
  • Toxic megacolon
  • Tuberculous peritonitis
  • Abdominal aortic aneurysms
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

36
Rheumatologic and Musculoskeletal Pain
  • Arthritis and arthropathies
  • Avascular necrosis
  • Polymyositis (most frequently seen)
  • Zidovidine myopathy
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

37
Skin
  • Various skin conditions cause pain
  • KS
  • Decubitus ulcers
  • Herpes simplex virus (HSV)
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

38
Peripheral Neuropathy
  • Symptomatic neuropathies occur in 15-50 of
    patients with HIV prevalence increases in
    advanced illness with higher HIV viral load,
    lower CD4 counts and older age
  • Martin C et al. Eur J Pain 2003 7 23.
  • Simpson DM et al. AIDS 2002 16 407.
  • Lopez L et al. Eur J Neurol 2004 11 97.

39
Neuropathies Associated with HIV Infection
  • Distal symmetrical polyneuropathy (DSP)
  • Antiretroviral toxic neuropathies (ATN)
  • Herpes zoster (HZ) and post-herpetic neuralgia
    (PHN)
  • Mononeuropathy multiplex (MM)
  • Diffuse infiltrative lymphocytosis syndrome
    (DILS)
  • Lumbrosacral polyradiculopathy (cauda equina
    syndrome)
  • Mononeuropathies
  • Inflammatory demyelinating polyneuropathies
  • Autonomic neuropathy
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

40
Distal Symmetrical Polyneuropathy (DSP)
  • One of most common HIV neuropathies presents in
    middle and late stages
  • Starts with tingling numbness in toes, spreads
    proximally from lower extremities
  • Painful dysesthesias or numbness occur
  • DTRs may be decreased or absent
  • Muscle weakness is not prominent
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

41
Antiretroviral Toxic Neuropathies (ATN)
  • Occurs at any stage of HIV infection
  • Indistinguishable from DSP, except for temporal
    association with initiation of antiretroviral
    medication
  • More likely than DSP to be painful, have abrupt
    onset and progress rapidly
  • Nucleoside reverse transcriptase inhibitors
    (NRTIs) are the class most associated with it
  • d drugs ddl, ddC, d4t
  • Mitochondrial toxicity may be mechanism
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

42
Herpes Zoster and PHN
  • HZ, shingles results from VZV reactivation
  • Occurs with age immunocompromised status
  • Acute HZ lasts days, healing for weeks PHN
    persists gt 30 days
  • PHN pain persists for months to years
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

43
Mononeuropathy Multiplex
  • MM occurs early or late in HIV infection
  • In early stages MM is immune mediated in
    advanced AIDS can be caused by infection with
    CMV, Hepatitis B or C, particularly when
    associated with cryoglobulinemia
  • Patients present with numbness, tingling,
    abnormal sensation, burning pain, dysesthesia or
    paralysis
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

44
Diffuse Infiltrative Lymphocytosis Syndrome
  • DILS characterized by persistent peripheral blood
    polyclonal CD8 lymphocyte expansion
  • See lymphocytic infiltration of parotid glands,
    lungs, lymph nodes, lacrimal glands, kidneys,
    muscles and nerves
  • Most common is salivary gland enlargement
  • Peripheral sensory neuropathy with profound
    muscle weakness is seen
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

45
Lumbosacral polyradiculopathy
  • Usually associated with CMV infection also seen
    with HSV infection, tuberculosis, syphilis or
    cryptococcal infection
  • Rapidly progressing cauda equina syndrome can
    occur with AIDS
  • Presents with severe back and leg pain associated
    with LE weakness
  • Numbness and tingling can begin in feet or saddle
    region progression occurs rapidly
  • Results in flaccid paralysis with incontinence
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

46
Mononeuropathies
  • Cranial neuropathies
  • Median at wrist
  • Ulnar at elbow
  • Peroneal at fibular head
  • Phrenic at diaphragm
  • Present with decreased sensation, tingling,
    burning pain, weakness and paralysis impairment
    of taste and hyperacusis
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

47
Inflammatory Demyelinating Polyradiculoneuropathy
  • Two major patterns
  • Acute inflammatory demyelinating polyneuropathy
    (AIDP) aka Guillain Barre syndrome (GBS)
  • Occurs at time of seroconversion (CD4 gt 500)
    evolves rapidly over days to weeks
  • Chronic inflammatory demyelinating polyneuropathy
    (CIDP)
  • Occurs in advanced stages of illness evolves
    over weeks
  • Motor deficit predominates over mild sensory
    symptoms
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

48
Autonomic Neuropathy
  • Common in HIV infection
  • 76-84 having some abnormality
  • Severity of autonomic dysfunction correlates with
    progression of HIV disease
  • Common symptoms include nausea, vomiting,
    orthostatic hypotension, heat intolerance,
    diarrhea, constipation, urinary incontinence,
    bladder dysfunction, impotence, anhidrosis or
    hyperhydrosis
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

49
Diagnosing DSP ATN
  • Labs unrevealing, but must exclude other causes
    of this neuropathy so order
  • B12 and folate levels, TSH, FBS, LFTs, BUN and
    Cr, Serum protein electrophoresis,
    immunoelectrophoresis, RPR or VDRL
  • CSF is acellular with slightly higher protein
  • EMG NVC show axonal sensory-motor
    polyneuropathy
  • Nerve biopsy shows axonal degeneration of long
    axons in distal regions density of unmyelinated
    fibers is reduced

50
Diagnosing HZ PHN
  • Distinctive rash
  • Direct immunofluorescent assay
  • Viral culture
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

51
Diagnosing MM
  • Screen for other causes CBC, lyme Ab titre,
    hepatitis screen, cryoglobulins, ESR
  • EMG NCV show asymmetric sensorimotor axonal
    polyneuropathy
  • CD4 lt200 suggests CMV infection
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

52
Diagnosing DILS
  • Peripheral CD8 gt 1000/microL CD8 lymphocytes
    gt60 of peripheral lymphocytes
  • ANA, anti-Ro and anti-La Abs absent
  • HLA DR5, DR6 or DR7 found in gt 50 DR2 in 36
  • Nerve biopsy shows focal loss of myelin fiber
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542

53
Diagnosing Lumbosacral Polyradiculopathy
  • LP with largely PML, elevated protein, glucose
    normal or reduced
  • CMV can be cultured in 50, but us CMV DNA PCR
    for rapid diagnosis
  • EMG and NVCs show primary axonal loss in
    lumbosacral roots with later denervation
    potentials in leg muscles
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

54
Inflammatory Demyelinating Polyradiculopathy
  • LP done for GBS or CIDP
  • CSP shows elevated protein, lymphocytic
    pleocytosis of 10-50 cells/mm3, normal glucose
  • EMG may be helpful for diagnosis of GBS CIDP
    NCV shows slow conduction, delayed latencies
    conduction blocks, reduced sensory motor
    amplitudes
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

55
Diagnosing Autonomic Neuropathy
  • Dysautonomia assessed by measuring
  • Pulse rate variability on standing, rest, deep
    breathing, valsalva maneuver, isometric exercise,
    cold face test and mental stress
  • Blood pressure is measured during standing,
    supine, resting and on valsalva
  • Policar, M Arumugam, V (2006). HIV and AIDS
    Pain, Weiners Pain Management A Practical Guide
    for Clinicians, 7th Ed., CRC Press, Boca Raton,
    529-542.

56
JCAHO Concerns New Standards Effective 1/1/01
  • Pain in USA is under treated
  • Pain is manageable must be treated
  • Patients have right to
  • Pain assessment
  • Adequate amounts of medication
  • Information to make informed choices
  • Facilities have responsibility to provide
    information, education, care continuity

57
Adverse Physiology of Pain
  • Increased heart rate and blood pressure
  • Altered respiratory function (tachypnea,
    atelectasis, pneumonia)
  • Lowered paO2 and risk of infection
  • Altered bowel function (ileus)
  • Risk of DVT with PE (pain limits ambulation)
  • Disuse atrophy and bone demineralization
  • Impaired immune function
  • Liebeskind JC. Pain 1991443-4
  • Akca O et al. The Lancet 199935441-42
  • AHCPR (1992). Acute Pain Management Guidelines

58
Pain Management 101
  • Dont delay management of pain for investigations
    or disease treatment
  • Unmanaged pain ? permanent nervous system changes
  • Amplify pain (spinal cord wind up)
  • Treat underlying cause if possible
  • Radiation for a neoplasm
  • Surgery for appendicitis
  • AMA (1999). The Project to Educate Physicians on
    End-of-life Care

59
Adverse Psychological Effects of Untreated Pain
  • Anxiety
  • Frustration
  • Depression
  • Desperation
  • Sleep deprivation
  • Suicidal ideation
  • Suffering

60
Measuring Desire for Death Among Patients with
HIV/AIDS
  • Schedule of Attitudes Toward Hastened Death
    demonstrated high reliability (195 patients with
    HIV/AIDS)
  • The total score significantly correlated with the
    clinician rating on
  • Desire for Death Rating Scale
  • ratings of depression (Beck Depression Inventory)
    and psychological distress (Brief Symptom
    Inventory)
  • Schedule of Attitudes Toward Hastened Death
    significantly correlated with
  • pain intensity
  • physical symptom distress
  • Rosenfeld B et al. Am J Psychiatry 1999 156(1)
    94-100

61
JCAHO On Assessment
  • Pain is a fifth vital sign
  • Pain will be routinely measured
  • Policies will define points of time when pain
    assessments are performed
  • Policies will define actions to be taken if pain
    intensities reach specified levels
  • Progress notes must reflect action taken

62
Measuring Pain
  • Pain is entirely subjective
  • Have to believe what is reported
  • Use many scales to measure pain
  • Descriptive analog scale
  • Numeric analog scale
  • Visual analog scale
  • Wong-Baker Faces scale
  • Everyone has to use same scale

63
Pain Assessment Tools
0-10 Numeric Pain Intensity Scale
Simple Descriptive Pain Intensity Scale
None
Moderate
Very Severe
Severe
Mild
Worst Possible
0-10 Numeric Pain Intensity Scale
None
Moderate
Worst Possible
Visual Analog Scale (VAS)
None
Pain as bad as itcould possibly be
Faces scale reprinted with permission from Patt
RB. Cancer Pain. Philadelphia JB Lippincott Co.
1993. Jacox A, et al. Management of Cancer Pain
Clinical Guideline No. 9. March 1994. AHCPR
Publication No. 94-0592.
64
Changing Philosophy About Pain Management
  • Patient actually may know what helps
  • Locus of control given to patient may provide
    best level of pain management
  • Patient can best determine end points
  • Patient is made part of the team
  • Opioids play an increasingly important role in
    long term pain management

65
Pain Types Responding to Opioid Analgesics
  • Acute chronic pain
  • Cancer non-cancer pain
  • Somatic, visceral and neuropathic pain
  • Doses for neuropathic pain may need to be greater
    than those for nociceptive pain
  • Fibromyalgia?
  • Opioids are the treatment for chronic pain
  • Bennett, RM. Mayo Clinic Proc 1999 74385-398
  • Bruera E et al. 1999. Opioids in Cancer Pain in
    Stein, C. (Ed.) Opioids in Pain Control, 309-324.
  • Watson CPN, Babul N. Neurology 1998501837-1841.

66
We Went to School Never Learned Opioids!
  • Most healthcare providers have little real
    understanding about opioid pharmacology
  • They know doses, names, structural formulae,
  • Sphincter of Oddi spasm is right answer for exams
  • What little they know is folklore in nature
    (medicine by mantra or by memorization)
  • Darvocet N100, 1-2 q 4-6 h prn mild-mod pain
  • Demerol 50-75 mg, IM q 4 h prn mod-severe pain

67
Clinical Concerns Regarding Use of Opioids for
Chronic Pain
  • Cognitive and psychomotor effects
  • Physical dependency episodic withdrawal
  • Tolerance to analgesic effects
  • Potential changes in pain modulation
  • Pain reinforcement
  • Risk of addiction
  • Use by patients for nonpain purposes
  • Savage SR. Med Clinics of North America 199983
    (3), 761-786.

68
Patient Concerns About Taking Opioids
  • Always lead to addiction
  • Cant tolerate the side effects
  • Once started cannot be stopped
  • Cant be treated for pain and the underlying
    process at the same time
  • If started too soon wont work when pain is very
    bad (no ability to titrate dose)

69
Questions About Opioids for Long Term Pain
Management
  • If opioids effectively relieve an individuals
    chronic pain, what other therapies should be
    tried before introducing opioids?
  • What level or intensity of chronic pain merits
    treatment with opioids?
  • Are there specific patients or contexts in which
    opioids should not be used because of
    unacceptable risks, despite their ability to
    relieve pain effectively?
  • How is effectiveness of opioid therapy of pain in
    individual patients measured?
  • Savage SR. Med Clinics of North America 199983
    (3), 761-786.

70
Opioids and Immunity
  • Before HIV/AIDS evidence suggested association of
    increased pathogenic susceptibility opioid use
  • Found in epidemiologic and case studies of heroin
    addicts with IV drug use
  • Considered inherent to their lifestyle
  • Infections thought to be due to contaminated
    material, metastatic sepsis, or by pathogens
    transmitted from person to person (sharing)
  • Alonzo NC Bayer BB. Infect Disease of North Am
    2002 16(3)

71
Opioids Immunity-2
  • Studies undertaken after recognition of AIDS had
    new perspective to elucidate effect of opioid use
    on immune system
  • Beginning in 1998, incidence of wound botulism in
    CA rose nearly 20-fold from historic level (0.5
    cases per year between 1951-1997)
  • Seen in addicts injecting black tar heroin
  • Alonzo NC Bayer BB. Infect Disease of North Am
    2002 16(3)

72
Opioids Immunity-3
  • Increased prevalence of bacterial, viral and
    parasitic infections in heroin users suggested
    immunological impairment
  • Especially cell-mediated immunity
  • Heroin users have higher rates of lymphadenopathy
    with extraordinary follicular hyperplasia,
    leukopenia, lymphocytopenia, drastic increase in
    CD8 cells, decrease in CD4 cells, suppressed
    absolute T-lymphocyte counts
  • Alonzo NC Bayer BB. Infect Disease of North Am
    2002 16(3)

73
Opioids Immunity-4
  • Heroin use associated with depressed monocyte
    adherence and chemotaxis, abnormal lymph node and
    thymus pathology elevated serum polyclonal
    immunoglobulin (primarily IgM IgG), false
    positive test for syphilis
  • Suggest being immunocompromised
  • Alonzo NC Bayer BB. Infect Disease of North Am
    2002 16(3)

74
Opioids Immunity-5
  • Opioid immunomodulation (morphine)
  • 90-150 mg oral morphine causes significant
    decrease in antibody-dependent cell cytotoxicity
    and NK-cell cytotoxicity, but no alteration of
    expression of Fc receptors on effector cells
  • Yeager MP et al. Clin Immunol Immunopathol
    199262(3)336-43
  • Morphine causes prolonged suppression of NK-cell
    cytotoxicity after 10 mg IM morphine, but not
    after 100 mg IM tramadol
  • Sacerdote P et al. Anesth Analg 2000901411-4.

75
Opioids Immunity-6
  • Methadone depresses T-cell function as measured
    by formation of T-rosettes in response to sheep
    erythrocytes, decreases granulocyte chemotaxis to
    fMLP, casein and activated plasma
  • Methadone-maintained patients have lower CD4 cell
    and CD4/CD8 cell ratio higher CD8 absolute
    cell count and of lymphocytes
  • Carballo-Dieguez A, Sahs J Goetz R. Am J Drug
    Alcohol Abuse 199420(3)317-29.
  • Prolonged methadone use reverses heroin
    use-induced immunosuppression
  • Novick DM et al. J Pharmacol Exp Ther
    1989250606-10.

76
Opioids Immunity-7
  • Human studies confounded by life style, stress,
    small numbers
  • Animal studies suggest opioid induced changes in
    hypothalamic-pituitary-adrenal (HPA) axis and
    activation of lymphoid organs innervated by
    sympathetic nervous system
  • Extensive morphine treatment of mice suppressed
    immune parameters by activation of the HPA axis
  • Morphine suppression of T-lymphocyte
    proliferation not attenuated by adrenalectomy or
    RU486 pretreatment
  • Bryant HU, Bernton EW Holaday JW. J Pharmacol
    Exp Ther 1988 245913-20.
  • Bryant HU et al. Endocrinology 19911283253-8.
  • Flores LR, Hernandez MC Bayer BM. J Pharmacol
    Exp Ther 19942681129-34.

77
Opioids Immunity-8
  • Brain and immune system communicate
  • Central application of morphine suppresses immune
    cell activities
  • Animals treated with opioids exhibit altered
    immune function
  • Humans exposed to opioids for pain management or
    maintained on methadone for drug addiction show
    either no effect or a suppressed immune system,
    depending on dosage, treatment duration
  • Alonzo NC Bayer BB. Infect Disease of North Am
    2002 16(3)

78
Milligrams Dont Matter
  • We must identify specific outcome(s)
  • Activities of daily living
  • Quality of life
  • Pain intensity
  • Patients taking high medication doses dont
    always have loss of control
  • Milligrams blood levels not all of story

79
Some Patients Need Larger Opioid Doses
  • There are no standard opioid doses
  • Patients experience their pain uniquely
  • Dosages not consistent due to individual
    variations in pain intensity, mechanisms of
    action, other factors
  • Patients need doses that relieve or modify pain
    experience without toxicity

80
Is Acetaminophen Poisonous?
  • Does patient drink alcohol beverages?
  • If so, daily APAP max. tolerance is 2-3 g
  • If not, daily APAP max. tolerance is 4 g
  • Perhaps APAP is nephrotoxic?
  • 500,000 mg (1000 tabs of Darvocet?, Vicodin?,
    etc.) in lifetime doubles ESRD risk
  • 2,500,000 mg in lifetime triples ESRD risk
  • APAP NSAIDs worse than APAP alone!
  • Perneger TV, Whelton PK, Klag MJ. NEJM
    1994331(25)1675-1679
  • Perhaps APAP is not nephrotoxic?
  • Moderate APAP use does not increase risk of renal
    dysfunction
  • Rexrode KM et al. JAMA 2001286315-321

81
Non-Steroidal Anti-Inflammatory Meds
  • Toxicities GI, renal, hepatic platelets
  • GI bleeds annually harm US arthritics
  • 107,000 hospitalized
  • 16,500 dead
  • Are COX-2 inhibitors less toxic?
  • Not free of renal toxicity, CHF, MI, HTN, CVA
    risks
  • No 20 year long term studies
  • Singh G et al. Arch Intern Med 19961561530
  • Singh G. Am J Med 1998105(1B)31S-38S

82
Adjunctive Therapy for Pain Control
  • Medications that supplement primary analgesics so
    utilized in pain management
  • may themselves be primary analgesics
  • use at any step of WHO ladder
  • Rarely discussed in osteoarthritis, common in
    fibromyalgia and other pain states
  • Co-analgesics should be utilized in conjunction
    with NSAIDs (COX-2 NSAIDs)
  • Alter neurotransmitters DA, NE, 5-HT
  • Alter receptor function GABA, NMDA

83
Adjuvant Medications
  • Anxiolytics (GABA)
  • Anticonvulsants (GABA, NMDA-receptors, Sodium
    channels)
  • Antidepressants (5-HT, NE)
  • Antipsychotics (DA blocking)
  • Psychostimulants (DA enhancing)

84
Lets Use Psychopharmacology!
  • We have tried every class available
  • Antidepressants, anticonvulsants, antipsychotics,
    anxiolytics stimulants
  • These are potent potentially toxic agents with
    increasing age illness
  • Confusion, delirium, dry mouth, etc.
  • Cardiovascular effects leading to falls,
    fractures, lacerations subdurals

85
CYP2D6, Codeine Codeine-like Opioids
  • Codeine must be converted to morphine
    hydrocodone to hydromorphone for analgesia
  • Without CYP2D6 there is no conversion to morphine
    and no analgesia
  • Congenitally absent in 7-10 of US whites, 3
    blacks 1 asians
  • Many common medications inhibit CYP2D6
  • Amiodarone, fluoxetine, haloperidol, paroxetine,
    propafenone, propoxyphene, qunidine, ritonavir,
    terbinafine, thioridazine
  • Supernaw RB. Am J Pain Management 200111 30-31.

86
Randomized Trial of Amitriptyline and Mexiletine
for Painful HIV Neuropathy
  • Randomized, double-blind, 10-week trial of 145
    patients assigned equally to amitriptyline,
    mexiletine, or placebo
  • Primary outcome measure was change in pain
    intensity between baseline and final visit
  • Improvement in amitriptyline group (0.31/-0.31
    units mean/-SD) and mexiletine group
    (0.23/-0.41) was not significantly different
    from placebo (0.20/-0.30)
  • Neither amitriptyline nor mexiletine provided
    significant pain relief in patients with
    HIV-associated painful sensory neuropathy.
  • Kieburtz K et al. Neurology 1998 Dec 51(6)
    1682-8

87
Acupuncture Amitriptyline for HIV-related
Peripheral Neuropathy-1
  • Randomized, placebo-controlled, 10 city trial
  • Each site enrolled patients into 1 option
  • modified double-blind 2 x 2 factorial design of
    standardized acupuncture regimen (SAR),
    amitriptyline, or combination compared with
    placebo
  • modified double-blind design of an SAR vs.
    control points
  • double-blind design of amitriptyline vs. placebo.
  • 250 with HIV-peripheral neuropathy
  • 239 Pts were in the acupuncture comparison
  • 125 in the factorial option
  • 114 in the SAR option vs. control points option
  • 136 patients were in amitriptyline comparison
  • 125 in the factorial option
  • 11 in amitriptyline option vs. placebo option
  • Shlay JC et al. JAMA 1998 Nov 11 280(18) 1590-5

88
Acupuncture Amitriptyline for HIV-related
Peripheral Neuropathy-2
  • Treatments given for 14 weeks
  • SAR vs. control points
  • Amitriptyline (75 mg/d) vs. placebo
  • Both therapies
  • Measured changes in mean pain scores at 6 14
    weeks using pain scale from no pain to extremely
    intense(outcome)
  • Patients in all 4 groups showed reduction in mean
    pain scores at 6 and 14 weeks compared with
    baseline values
  • Neither acupuncture nor amitriptyline was more
    effective than placebo in relieving pain caused
    by HIV-related peripheral neuropathy
  • Shlay JC et al. JAMA 1998 Nov 11 280(18) 1590-5

89
Acupuncture Amitriptyline for HIV-related
Peripheral Neuropathy-3
  • For both the acupuncture and amitriptyline
    comparisons, changes in pain score were not
    significantly different between the groups
  • At 6 weeks, the estimated difference in pain
    reduction for patients in the SAR group compared
    with those in the control points group (a
    negative value indicates a greater reduction for
    the "active" treatment) was 0.01 (95 confidence
    interval CI, -0.11 to 0.12 P.88) and for
    patients in the amitriptyline group vs. those in
    the placebo group was -0.07 (95 CI, -0.22 to
    0.08 P.38)
  • At 14 weeks, the difference for those in the SAR
    group compared with those in the control points
    group was -0.08 (95 CI, -0.21 to 0.06 P.26)
    and for amitriptyline compared with placebo was
    0.00 (95 CI, -0.18 to 0.19 P.99)
  • Shlay JC et al. JAMA 1998 Nov 11 280(18) 1590-5

90
Lamotrigine
  • RDBPCT of patients with HIV-associated DSP
    received lamotrigine or placebo during a 7-week
    dose escalation phase followed by a 4-week
    maintenance phase
  • 92 were randomized in stratum receiving
    neurotoxic ART and 135 in stratum not receiving
    neurotoxic ART
  • Mean change from baseline in Gracely Pain Scale
    for average pain was different between groups at
    end of maintenance phase in either stratum, but
    slope of change in score for average pain
    reflected greater improvement with lamotrigine
    than with placebo in stratum receiving neurotoxic
    ART (p 0.004) as did mean change from baseline
    scores on VAS and McGill Pain Assessment Scale
  • Simpson DM et al. Neurology 200360(9)

91
Intrathecal Ziconotide
  • Ziconotide is a selective N-type calcium channel
    blocker inhibiting neurotransmitter release
  • 108 patients with refractory pain despite use of
    systemic or intrathecal opioids in the titration
    phase, mean VAS scores improved more in
    ziconotide group (51) than placebo group (18)
    serious adverse effects were more common in
    ziconotide group (31) than placebo group (10)
  • 48 patients receiving ziconotide proceeding to
    maintenance phase had benefit of ziconotide
    continued
  • Doggrell AS. Expert Opin Investing Drugs
    200413(7)875-7

92
Intrathecal Ziconotide-2
  • DBPCRT with 32 sites and 111 patients ziconotide
    was titrated over 5-6 days, followed by 5-day
    maintenance phase for responders and crossover of
    nonresponders to opposite treatment group
  • 67 of 68 patients receiving ziconotide 38 of 40
    patients receiving placebo were taking opioids at
    baseline
  • 36 had used intrathecal morphine
  • VASPI scores were 73.6 mm in ziconotide group and
    77.9 mm in placebo group
  • Mean VASPI scores improved 53.1 in ziconotide
    group and 18.1 in placebo group (Plt.001)
  • Pain relief was moderate to complete in 52.9 on
    ziconotide, 17.5 in placebo group (Plt.001)
  • 5 on ziconotide had complete pain relief, 17.5
    on placebo
  • Staats PS et al. JAMA 200429(1)63-70.

93
Are Opioids Addictive for Everybody?
  • No! Watch out for cherry syrup addicts!
  • Opioid addicts should not get opioids without
    consideration of the facts
  • Odds of non-addict addiction from prescribed
    medications is 1/800 to lt1/10,000
  • CIIIs not encoded for less problems
  • Result in conditioning to use
  • CIIIs denatured to limit amount of opioid taken

94
Do All Opioid Medication Users Get Into Trouble?
  • Low back pain study for 12 months
  • Osteoarthritis study for 18 months
  • Methadone maintenance for a lifetime
  • Multi-gram doses in hospice patients
  • EPEC curriculum and end-of-life care
  • We have no predictive tools yet

95
Long Term Opioid Administration Stable Doses
Pain Control, Reduction in Side Effects
  • 106 patients enrolled (76 women, 42 gt 64 yrs)
  • Baseline median dose 20 mg/d baseline median
    pain intensity 2 (moderate)
  • Median daily dose increased until week 16, where
    it stabilized at 40 mg/d
  • No further increases for one year
  • Increases in dose were accompanied by reduction
    in pain
  • Median pain intensity fell to stable level within
    2 weeks and remained slight to moderate for gt 1
    yr
  • Side effects lessened between 8th 40th weeks
  • Especially for sleepiness and sick to stomach
  • Roth, S. et al. 1998 APS Poster Board 168.

96
ATC CR Oxycodone for Osteoarthritis Pain
  • 133 pts were randomized to placebo, 10 mg or 20
    mg q 12 h for 14 days
  • 106 pts enrolled in open-label study for 6
    months then Tx for optional 12 months
  • During long-term Tx mean dose remained stable at
    40m mg/d
  • 58 pts completed 6 mos, 41 completed 12 mos, 15
    completed 18 mos
  • Roth SH et al. Arch Internal Med
    2000160853-860.

97
US Trends in Medical Use Abuse of Opioids
(1990-96)Joranson DE et al. JAMA
2000283(13)1710-1714
  • Increased use
  • Hydromorph 19
  • Fentanyl 1168
  • Morphine 59
  • Oxycodone 23
  • Decreased use
  • Meperidine 35
  • Changes in abuse
  • Down 15
  • Down 59
  • Up 3
  • Down 29
  • Down 39

98
Estimated of Opioid ED Drug EpisodesYear-End
2002 ED DAWN Data, SAMHSA
Drug 1994 1995 1996 1997 1998 1999 2000 2001 2002
codeine 9439 8732 7594 7869 6620 4974 5295 3720 4961
fentanyl 28 22 34 203 286 337 576 710 1506
hydrocod 9320 9686 11419 11570 13611 15252 20098 21567 25197
meper 925 1045 876 864 730 882 1085 665 722
methad 3252 4247 4129 3832 4810 5426 7819 10725 11709
morph 1099 1283 864 1300 1955 2217 2483 3402 2775
oxycod 4069 3393 3190 5012 5211 6429 10825 18409 22397
propoxy 6731 6294 5889 6502 5826 5632 5485 5361 4676
99
What Defines Addicts?
  • Fusion of anxiety and denial
  • Constantly anxious about availability of drug
    always trying to obtain more of it
  • No insight into toxicity of drug on their health,
    life, relationships, etc
  • No awareness that control has been lost
  • Intend to quit when a little bit sicker

100
Response Styles Specific to Substance Abuse
  • Disacknowledgment
  • Misappraisal
  • Denial
  • Exaggeration
  • Rogers R, Kelly KS 1997. Denial and misreporting
    of substance abuse. In R Rogers (Ed.) Clinical
    Assessment of Malingering and Deception. New
    York, NY Guilford Press.

101
Suggestive Signs of Addiction during Opioid
Therapy of Pain-1
  • Loss of control
  • Compulsive overuse, unable to take medications as
    prescribed
  • Frequently runs out of medication early despite
    dose agreement
  • Frequently reports lost or stolen prescriptions
  • Solicits multiple prescribers
  • Uses multiple pharmacies to fill prescriptions
  • Savage SR. Med Clinics of North America
    199983(3), 761-786.

102
Suggestive Signs of Addiction during Opioid
Therapy of Pain-2
  • Preoccupation with drug use
  • Noncompliant with other treatment recommendations
  • Misses other appointments, always arrives for
    opioid prescriptions
  • Uses street drugs, involved with street culture
  • Preference for short-acting or bolus dose
    medications
  • Reports no relief with other medications or
    treatments
  • Reports allergies to all other medications
  • Savage SR. Med Clinics of North America
    199983(3), 761-786.

103
Suggestive Signs of Addiction during Opioid
Therapy of Pain-3
  • Adverse consequences of opioid use
  • Declining function despite apparent analgesia
  • Observed to be frequently intoxicated or high
  • Persistently over sedated
  • Savage SR. Med Clinics of North America
    199983(3), 761-786.

104
Pain Addiction DifferencesSchnoll SH, Finch J.
J Law Med Ethics 1994 22252-256
  • Pain patients
  • Not out of control with medications
  • Meds improve QOL
  • Aware of SEs
  • Concerned about medical problems
  • Follow the Tx plan
  • Have meds left over
  • Addicted patients
  • Out of control with medications
  • Meds decrease QOL
  • Unconcerned by SEs
  • Denial about medical problem
  • Wont follow Tx plan
  • Never have meds left

105
Opioids Getting Patients Into Trouble . . .
  • Meperidine (Nor-meperidine)
  • gt 400 mg/d causes confusion, delirium, myoclonus,
    seizures with renal disease
  • Mixed agonist-antagonists
  • Delirium, hallucinations, psychosis with
    continued use (8-12 Talwin? /d, 1 bottle Stadol?
    nasal spray/d)

106
. . . Opioids Getting Patients Into Trouble
  • Propoxyphene (nor-propoxyphene)
  • Confusion, delirium and other bad outcomes
  • Fentanyl transdermal
  • Heat increases the delivered dose (overdose)
  • Cachexia makes absorption erratic (wt lt 110 lbs)
  • Addicts chew, smoke or shoot the fentanyl

107
JCAHO Meperidine
  • Its pharmacists responsibility to limit access
    to meperidine in LTC facilities (JCAHO)
  • Use ordering as an educational opportunity
  • Limit duration of use
  • APS stop meperidine after two consecutive days
  • Limit overall daily dosage
  • APS limit (1999) 600 mg/d
  • But if pt gt60 yrs, try to limit to lt400 mg/d
  • APS (1999). Principles of Analgesic Use in the
    Treatment of Acute Pain and Chronic Cancer Pain
    A Concise Guide to Medical Practice, Fourth
    Edition.

108
Morphine May Not Be the Gold Standard Any
Longer
  • Consider other gold standards we dont use that
    much today
  • Chlorpromazine (Thorazine?) for psychosis
  • Amitriptyline (Elavil?) for depression
  • Trend to use semi-synthetic opioids
  • Fentanyl
  • Oxycodone
  • Hydromorphone

109
Morphine Metabolites
  • Metabolites are eliminated renally
  • Unmetabolized morphine 2-8
  • Glucuronide metabolites 50-80 (WgtM)
  • Morphine-3-glucuronide
  • Devoid of analgesic activity
  • Antagonist to morphine analgesic activity
  • peripheral site of antagonism (NMDA-receptors)
  • May induce allodynia and hyperalgesia
  • CNS excitation leads to agitation, confusion,
    delirium and seizure thought to be responsible
    for myoclonus
  • Morphine-6-glucuronide
  • Same affinity for mu-1 receptor (analgesic
    activity) as morphine
  • Others metabolites pathways
  • Demethylation (Normorphine)
  • Conjugation, diglucuronidation, sulfonation

110
Hydrocodone Combinations
  • All are CIIIs immediate release in USA
  • Stable blood levels only with 4-6 hour use
  • All contain some APAP or NSAID
  • Is hydrocodone really strong enough by itself?
  • Are liver kidney damage possible with use?
  • Many states are tracking hydrocodone
  • Most abused drug in NV (42 M doses in 2000)
  • Las Vegas Sun September 9, 2001E1.
  • Las Vegas Sun October 7, 2001E1.

111
Is Oxycodone Enough?
  • It is a pure opioid agonist
  • Semi-synthetic derivative of morphine
  • Many assumed that oxycodone was not very strong,
    because it was denatured (APAP)
  • No established ceiling dose for oxycodone
  • Record dose is 9600 mg / day base with 1200 mg q
    h for breakthrough pain (ovarian Ca patient)
  • Metabolites not linked to CNS excitation

112
Role of Hydromorphone
  • Semi-synthetic derivative of morphine
  • More potent than morphine
  • Less CNS toxicity than morphine
  • more than oxycodone fentanyl
  • Available as oral injectable forms
  • Oral
  • Short-acting 2 mg, 4 mg, 8 mg
  • Long-acting controlled release approved
    (Palladone ?)
  • Injectable up to 10 mg/ml (Dilaudid HP?)
  • Record dose is 60-600 mg IV/h for pain of pelvic
    sarcomaequivalent to 900-9000 8 mg po tabs/d

113
Fentanyl
  • Fentanyl transdermal (Duragesic?)
  • peak effect after application ? 24 hours
  • patch lasts 4872 hours
  • must ensure adherence to skin, thermal and pain
    stability, patients weigh gt 110 lbs
  • Alternative for patients who cannot tolerate
    oral, parenteral or rectal routes (very few) or
    are allergic to other opioids (fentanyl is
    synthetic)
  • Oral (Actiq?)
  • 25-50 bioavailability (25 from buccal
    absorption, 25 from absorption of fentanyl in
    swallowed saliva after 1st pass effect)

114
Short- vs. Long-acting
  • It does make a difference
  • We have to pharmacologically choose
  • We want to maintain stable blood levels for most
    conditions
  • Hypertension
  • Diabetes
  • Infection
  • Seizures
  • Pain

115
Long-acting Opioids
  • Fentanyl (Duragesic? transdermal patches)
  • Hydromorphone (Palladone?)
  • Morphine
  • MS Contin?, Oramorph?, Kadian?, Avinza?
  • Oxycodone (OxyContin?)
  • Oxymorphone (in development)
  • Tramadol (in development)

116
Are Controlled Release Meds Only for Cancer Pain?
  • No, they are for pain necessitating more than a
    few doses of medication for relief!
  • Immediate release medications are best for single
    dose administration or breakthrough
  • What medication used for any length of time
    shouldnt be given as CR?
  • Insulin NPH, Lente, etc.
  • Cardiovascular CR, XL, etc.

117
Are Controlled Release Meds Only for Chronic
Pain
  • No, for painful conditions requiring more than a
    few doses of medication!
  • When dont we want pain well controlled?
  • Why not use CR medications for post-op pain or
    rehabilitation?
  • When doesnt the patient want pain relief?
  • Can we shorten the length of rehabilitation?
  • Why not achieve best pain control with least
    medication by using CR medications?
  • Reuben SS et al. Anesthes Analgesia
    1999881286-1291
  • Cheville A et al. J Bone Joint Surgery
    200183-A(4)572-576

118
What Is So Bad About Single Entity Opioid
Analgesics?
  • CIIs are not less addictive that CIII-Vs
  • Addiction is a state of mind, not physiology
  • CIIs require careful record keeping
  • Have to at least write out the prescription
  • CII prescriptions alone do not trigger more
    investigations than CIIIs

119
Are CIIIs Really Easier to Use?
  • Can be telephoned to the pharmacy
  • Did physician obtain a proper history?
  • Did physician do a good faith examination?
  • Did physician write a progress note for Rx?
  • Did physician arrange for follow-up care?
  • Dont have to write out the prescription
  • Why practice with less than all options?

120
Are Narcs After Opioid Prescribers in General?
  • S. CA 0.5 of 90 FTEs in the S. CA Bureau of
    Narcotic Enforcement for prescribing
  • Review rate of triplicate prescriptions
  • 8 since 1940 but only 1.7 recently
  • NV prescribe to non-patients (yourself, family
    members, lovers), phone in 1200 CIIIs/mo but see
    no one or advertise RX price to get in trouble
  • AZ UT examine number of pills/prescription
  • Pills have intrinsic street value
  • Opioid schedule not the issue

121
What About Opioids for Known Substance Abusers
  • Opioids for HIV pain control in patients with
    substance abuse history raises issues
  • How to treat pain in people who have a high
    tolerance to narcotic analgesics
  • How to mitigate this populations drug-seeking
    and potentially manipulative behavior
  • How to deal with patients who may offer
    unreliable medical histories or who may not
    comply with treatment recommendations
  • How to counter the risk of patients spreading HIV
    while high and disinhibited
  • Breitbart W, Passik SD Rosenfeld BD (1999).
    Cancer, mind spirit. Textbook of Pain, 4th Ed.,
    1065-1112.

122
Approach to Pain Management for Substance
Abusers-1
  • Substance abusers deserve pain control we have
    an obligation to treat pain suffering for all
    our patients
  • Accept and respect the report of pain
  • Be careful about the label of substance abuse
    distinguish between tolerance, physical
    dependence, and addiction (psychological
    dependence)
  • Not all substance abusers are the same
    distinguish between active users, those in
    methadone maintenance and those in recovery
  • Breitbart, W
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