# Presentation: 201161

## 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  _*Merck*_ _*Manual*_* *published in 1899. _* *_

## 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.

##  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,

- 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

## 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

- 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

- Anxiety

- Depression

- Psychological Factors

- Pathological Process

- Physical Factors

**TIME**

*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

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