Chronic Pain

1
Chronic Pain

• Lee S. Simon, MD
• Division Director
• Analgesic, Anti-inflammatory and Ophthalmology
  Drug Products
• ODEV, CDER, FDA

2
PAIN

• Pain is always a subjective experience
• Everyone learns the meaning of pain through
  experiences usually related to injuries in early
  life
• As an unpleasant sensation it becomes an
  emotional experience
• Pain is a significant stress physically,
  emotionally

3
Pain

• In one hundred years there has been clear
  progress in the field defining painful disease
  states and syndromes along with delineating
  appropriate therapy as shown by a comparison of
  the Merck Manual in 1999, the Centennial Edition,
  with the indices for pain and analgesics in the
  original Merck Manual published in 1899.

4
INDICATIONS.Pain.-See also, AfterPains,
Anesthesia, Boils, Chest Pains, Colic,
Gastralgia, Headache, Hepatalgia, lnflammat i o n
, Lumbago, Myalgia, Neuralgia, Neuritis.
Odontalgia, Otalgia, Ovarian Neuralgia,
Rheumatisrn, etc. Also lists of Analgesics,
Anesthetics and Narcotics

• Acetanilid, Acid, Carbolic. Aconite. Aconitine_
  Ammonium Iodide. Atropine. Belladonna. Camphor,
  Monobromated. Camphor-phenol. Cannabis Indica.
  Chloroform, Chloral Hydrate. Chloral-Camphor.
• Cocaine
• Codeine
• Conium.
• Duboisine.
• Ethyl Chloride spray.
• Exalgine.
• Gelseminine_
• Guaiacol_
• Hyoscyamine_
• Ichthyol
• Merck Manual 1899

• Iodine.
• Iodoform.
• Iron.
• Manganese Dioxide.
• menthol
• Methyl Chloride Spray.
• Morphine.
• Neurodin_
• Opium.
• Peronin.
• Phenacetin.
• Potassium Cyanide
• Salipyrine.
• Solanine In gastric pain.
• Stramonium_
• Triphenin.
• Tropacocaine.

5
INDEX

• Pain, 13571, 1363-1374 (see also Neuralgia)
• abdominal, 257-261, 259t, 260t (see psychogenic,
  1363, 1373-1374, 1511 (also Abdomen, pain in)
• in pulmonary embolism, 1602
• acute, 1363
• radicular, 1488-1489
• in acute intermittent porphyries, 190 rectal, 339
• in angina pectoris, 1663 shoulder, 478-479, 507
• with aortic dissection, 1602 somatogenic, 1363
• in appendicitis, 265 stump, 1371-1372
• in avascular necrosis 453-454 in subacute
  thyroiditis, 97
• in ball of foot, 488-489
• testicular, 1805
• Merck Manual 1999 Centennial Edition

• bladder, 1805
• after tooth extraction, 770
• cancer, 979 1371 treatment of
• in carcinoid tumor, 217
• acupuncture for, 2495
• cardiac., 1601-1602
• cervical traction for, 2495
• in carpal tunnel syndrome, 1492-1493 cold for,
  2495
• chest, 516-517 (see also Chest, pain in) in
  dying patient, 2510-2511
• in cholelithiasis, 401
• electrical stimulation for, 2495
• chronic, 1363
• heat for, 2494-2495, 24941
• dental, 746, 760, 769-770
• massage for, 2495
• in dying patient, 2510-2511
• nondrug analgesic approaches in,

6

• ear, 667-668, 667t, 6681 1370, 1370t
• evaluation of, 1363-1364
• nonopioid analgesics in,1364-1365,
• eye, 703 1364t
• face, in trigeminal neuralgia, 1457, 1460
• opioid analgesics in, 1365-1370,
• ' in fibromyalgia, 481 - 1366t-1368t
• foot, 482-489 during rehabilitation, 2493-2497,
• gastrointestinal (see Abdomen, pain in) 2494t
• head (see Headache) vulvar, 1947
• heel, 485-488 painful fat syndrome 1798

• in hemophilia, 912 Paint, poisoning with, 2635t
• hip, in children, 2403 Paint thinner, poisoning
  with,
• kidney, 1804-1805 in children, 2280-2281
• lower back, 475-478
• sports-related, 503-505, 5041
• menstrual, 1933 hyperplasia of, 753t
• 'in metatarsophalangeal joints, 488-489
• in myocardial infarction, 1669
• in myocardial ischemia, 1601-1602
• Pallidotomy, 1469
• myofascial, 481, 774-775
• neck, 474-475 abscess of, 495

7

• neuropathic, 1363, 1371-1373
• fibromatosis of (Dupuytren's contracture)
• nociceptive, 1363 t, 491
• in obstructive uropathy, 1827
• in osteoarthritis, 451
• patellofemoral, 501-502, 502f, 503t
• pelvic, 1944-1948, 1945t
• pericardial, 1602 1456-1457, 1458t

8
Merck Manual 1999 Index for Analgesics

• Analgesia
• in acute post-operative pain, 1370-1371
• in cancer pain syndromes, 1371
• in dying patient, 2510-2511
• in elderly, 2602t 26041, 2610
• fetal effects of, 2024
• for labor, 2028
• in migraine, 1377, 1377t
• nephrotoxicity of, 1878, 1880t, 1881,1882t

• in neuropathic pain syndromes, 1371-1373
• nonopioid drugs for, 1364-1365, 1364t
• NSAIDs for, 13641365, 1364t
• opioid drugs for, 1365-1370,-1366t,1368t
• in tension headache, 1378

9

• However far we have come in furthering our
  description of disease states, as you can see
  many of the drugs used 100 years ago remain the
  drugs we use today
• opiates
• NSAIDs
• sedatives
• muscle relaxants

10
Various Descriptors of Pain
Somatic pain caused by the activation of pain
receptors in either the cutaneous (the body
surface) or deeper tissues (musculoskeletal
tissues). Visceral pain pain that is caused by
activation of pain receptors from infiltration,
compression, extension or stretching of the
thoracic, abdominal or pelvic viscera (chest,
stomach and pelvic areas). Neuropathic pain
caused by injury to the nervous system either as
a result of a tumor compressing nerves or the
spinal cord, or cancer actually infiltrating into
the nerves or spinal cord.
11
Various Descriptors of Pain

• Mild ??
• Moderate ??
• Severe ??
• Although descriptive, does not provide rigor
  perhaps these should be used to modify acute and
  chronic pain indications to allow patients to
  understand, but how do you measure what is mild,
  moderate, severe ultimately it is the bias of
  the agency, investigators, sponsors to suggest
  which is which.

12
Various Descriptors of Pain

• Acute pain short-lasting and manifesting in
  objective ways that can be easily described and
  observed. It may be clinically associated with
  diaphoresis and tachycardia. It can last for
  several days, increasing in intensity over time
  (subacute pain), or it can occur intermittently
  (episodic or intermittent pain). Usually related
  to a discreet event for onset post op, post
  truama, fracture, etc
• Chronic pain Long-term and typically defined if
  it lasts for gt three months. It is more
  subjective and not as easily clinically
  characterized as acute pain and is more
  psychological. This kind of pain usually affects
  a person's life, changing personality, their
  ability to function, and their overall lifestyle.

13
Various Descriptors of Pain

• General pain
• Has been broadly used in the past (92 Pain
  guidance) however, acute and chronic indications
  use different models, may be mechanistically
  different, and have different safety issues.
  Furthermore, the psychological component clearly
  separates the acute pain experience from a
  chronic one.

14

• Chronic pain has a psycho-social component that
  must be dealt with before depression becomes a
  part of the clinical picture. Chronic pain
  should be recognized as a multi-factorial disease
  state requiring intervention at many levels.
• A.G. Lipman, Cancer Nursing, 239, 1980 (6).

15
Dimensions of Chronic Pain
Loneliness
Hostility
Social Factors
Depression
Anxiety
TIME
Psychological Factors
Pathological Process
Physical Factors
A.G. Lipman, Cancer Nursing, 239, 1980
16
Trial Design

• Looking for models or disease states
• Osteoarthritis
• Chronic low back pain
• Fibromyalgia
• Neuropathic pain
• Diabetic neuropathy, amyotrophy
• Cancer pain
• Temperomandibular pain
• Peripheral vascular disease
• Mechanisms or mechanistic approaches

17
Trial Design

• Possible indications
• For one disease or model
• An example Signs and symptoms of OA
• Two replicate randomized and controlled trials
• Three co-primary outcomes at which each must win
• Pain, function and patient determined global
• Superiority to placebo, or.
• Superiority to active comparator

18
Trial Design

• Possible indications
• For an organ system
• For example improvement in pain of the
  musculoskeletal system
• Three models or diseases
• Low back pain
• Osteoarthritis
• Fibromyalgia
• Need two replicate RCTs for each model or
  disease
• Need three co-primary outcomes pain, function and
  patient determined global each must win as
  either superior to placebo, superior to active
  comparator
• The label will also reflect approval of all
  diseases/models studied

19
Trial Design

• Possible indications for example Chronic pain
• Requires three models, disease states, mechanisms
• Replicate trials in each model, should be in
  disparate diseases (eg musculoskeletal, cancer,
  neuropathic)
• Must measure pain, patient global, and some
  functional outcome
• Must be superior to placebo in all three
  outcomes, superior to active comparator
• Label will reflect approval for the broad
  category limited by safety considerations
• Label will thus, based on data, demonstrate that
  therapy is approved for the indication of chronic
  pain but also the three diseases/models studied

20
Trial Design

• Mechanistic approach
• Dont know YET how to do this
• Dont really know the models
• Possible examples
• Alteration of wind-up by inhibition of NMDA
  receptors
• Alteration of brain plasticity
• Alteration of early markers that predict specific
  and verified CLINICAL outcomes

21
(No Transcript)
22
(No Transcript)