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