Chronic Pain • Lee S. Simon, MD • Division Director • Analgesic, Anti-inflammatory and Ophthalmology Drug Products • ODEV, CDER, FDA
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
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 MerckManualpublished in 1899.
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. 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
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, INDEX
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
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
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 Merck Manual 1999: Index for Analgesics
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
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.
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 Depression Anxiety TIME Psychological Factors Pathological Process PhysicalFactors A.G. Lipman, Cancer Nursing, 2:39, 1980
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
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 system • Three models or diseases • Low back pain • Osteoarthritis • Fibromyalgia • Need two replicate RCT’s 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
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
Trial Design • Mechanistic approach • Don’t know YET how to do this • Don’t 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