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Chronic Pain

Lee S. Simon, MD
Division Director
Analgesic, Anti-inflammatory and
Ophthalmology Drug Products
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,
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.
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. Iodine.

Aconitine_ Ammonium Iodide. Iodoform.
Atropine. Belladonna. Camphor, Iron.
Monobromated. Camphor-phenol.
Cannabis Indica. Chloroform, Manganese Dioxide.
Chloral Hydrate. Chloral-Camphor. menthol
Cocaine Methyl Chloride Spray.
Codeine Morphine.
Conium. Neurodin_
Duboisine. Opium.
Ethyl Chloride spray. Peronin.
Exalgine. Phenacetin.
Gelseminine_ Potassium Cyanide
Guaiacol_ Salipyrine.
Hyoscyamine_ Solanine: In gastric pain.
Ichthyol Stramonium_
Merck Manual 1899 Tropacocaine.
Pain, 13571, 1363-1374 (see bladder, 1805
also Neuralgia) after tooth extraction, 770
abdominal, 257-261, 259t, 260t (see cancer, 979 1371 treatment of
psychogenic, 1363, 1373-1374, in carcinoid tumor, 217
1511 (also Abdomen, pain in) acupuncture for, 2495
in pulmonary embolism, 1602 cardiac., 1601-1602
acute, 1363 cervical traction for, 2495
radicular, 1488-1489 in carpal tunnel syndrome, 1492-
in acute intermittent porphyries, 190 1493 cold for, 2495
rectal, 339 chest, 516-517 (see also Chest,
in angina pectoris, 1663 shoulder, pain in) in dying patient,
478-479, 507 2510-2511
with aortic dissection, 1602 in cholelithiasis, 401
somatogenic, 1363 electrical stimulation for, 2495
in appendicitis, 265 stump, 1371- chronic, 1363
heat for, 2494-2495, 24941
in avascular necrosis 453-454 in
dental, 746, 760, 769-770
subacute thyroiditis, 97
massage for, 2495
in ball of foot, 488-489
in dying patient, 2510-2511
testicular, 1805
nondrug analgesic approaches in,
Merck Manual 1999 Centennial Edition
ear, 667-668, 667t, 6681 1370, in hemophilia, 912 Paint, poisoning
1370t with, 2635t
evaluation of, 1363-1364 hip, in children, 2403 Paint thinner,
nonopioid analgesics in,1364-1365, poisoning with,
eye, 703 1364t kidney, 1804-1805 in children, 2280-
face, in trigeminal neuralgia, 1457, 2281
1460 lower back, 475-478
opioid analgesics in, 1365-1370, sports-related, 503-505, 5041
' in fibromyalgia, 481 - 1366t-1368t menstrual, 1933 hyperplasia of,
foot, 482-489 during rehabilitation, 753t
2493-2497, 'in metatarsophalangeal joints, 488-
gastrointestinal (see Abdomen, pain 489
in) 2494t in myocardial infarction, 1669
head (see Headache) vulvar, 1947 in myocardial ischemia, 1601-1602
heel, 485-488 painful fat syndrome Pallidotomy, 1469
1798 myofascial, 481, 774-775
neck, 474-475 abscess of, 495
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
Merck Manual 1999: Index for Analgesics

in acute post-operative pain, 1370- in neuropathic pain syndromes,
1371 1371-1373
in cancer pain syndromes, 1371 nonopioid drugs for, 1364-1365,
in dying patient, 2510-2511 1364t
in elderly, 2602t; 26041, 2610 NSAIDs for, 13641365, 1364t
fetal effects of, 2024
opioid drugs for, 1365-1370,-
for labor, 2028
in migraine, 1377, 1377t
in tension headache, 1378
nephrotoxicity of, 1878, 1880t,
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:
muscle relaxants
Various Descriptors of Pain

Somatic pain: caused by the activation of pain receptors in either

the cutaneous (the body surface) or deeper tissues (musculoskeletal

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.
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.
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 >

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.
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.
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, 2:39, 1980 (6).

Dimensions of Chronic Pain

Loneliness Hostility

Social Factors

Anxiety Depression

Psychological Factors

Pathological Process

Physical Factors

A.G. Lipman, Cancer Nursing, 2:39, 1980

Trial Design
Looking for models or disease states
Chronic low back pain
Neuropathic pain
Diabetic neuropathy, amyotrophy
Cancer pain
Temperomandibular pain
Peripheral vascular disease
Mechanisms or mechanistic approaches
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
Trial Design
Possible indications
For an organ system
For example: improvement in pain of the musculoskeletal
Three models or diseases
Low back pain
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
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
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
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
Alteration of brain plasticity
Alteration of early markers that predict specific
and verified CLINICAL outcomes