The Challenge of Relieving Pain
by Dori Stehlin

    The lucky among us have only an occasional headache. For others, pain is  
a constant, though unwelcome, companion.
    Relieving pain is sometimes simple, sometimes impossible. It depends on   
the source of the pain and it may also depend on the person.

Everyday Aches and Pains
    There are three main nonprescription choices for pain relief--aspirin,    
acetaminophen (Datril, Tylenol and others), and ibuprofen (Motrin IB, Advil,  
Nuprin, and others). All three block the production of chemicals called       
prostaglandins, which the body usually releases when cells are injured.       
Prostaglandins are believed to play an important role in the pain, heat,      
redness, and swelling that occur following tissue damage.
    So what's the best choice for your headache, pulled muscle, or menstrual  
cramps?
    When it comes to mild, nonspecific pain, headaches, or menstrual          
discomfort, "all three [nonprescription pain relievers] are quite useful,"    
says Patricia Love, M.D., a rheumatologist with FDA's Center for Drug         
Evaluation and Research. "There are probably persons who are not able to      
detect a difference in the effectiveness of the OTC products."
    It has been suggested, Love says, that aspirin or ibuprofen may be more   
effective than acetaminophen for pain caused by inflammation or mild          
menstrual discomfort because they have more prostaglandin-blocking effects.   
(For more information on menstrual cramps, see "Taming Menstrual Cramps" in   
the June 1991 FDA Consumer.) "Our best advice at present is that, for mild    
pain, individuals may use what works best and is safe for them," says Love.
    In other words, what doesn't cause them problems.
    Because prostaglandins play a role in protecting the stomach lining from  
being attacked by the acid of digestive fluid, aspirin, ibuprofen, and,       
apparently to a lesser extent, according to Love, acetaminophen may cause     
stomach irritation, ulcers or bleeding. "If you have a history of stomach     
disorders, first talk to your doctor [before taking a nonprescription pain    
reliever]," says Love.
    For some people who take aspirin, stomach irritation may be decreased by  
taking either enteric-coated aspirin, buffered aspirin, or other modified     
aspirin derivatives such as choline salicylate or magnesium salicylate.
    Buffered aspirin contains an ingredient that neutralizes some of the      
digestive system's acid and, therefore, may produce less irritation than      
plain aspirin.
    Coated aspirin dissolves mainly in the intestine. (Uncoated aspirin       
dissolves in the stomach.) In theory, that difference may mean less stomach   
irritation says Love. But, she adds, it still depends on an individual's      
metabolism. For example, some people can't digest the coating, so while they  
don't get any stomach irritation, they don't get any benefit either. The      
aspirin passes out of the body undigested and unabsorbed.
    People who can't take aspirin because of allergic reactions (e.g., rash,  
asthma, anaphylaxis) generally can't take ibuprofen either. For them,         
acetaminophen may be the only nonprescription choice. 
    "Persons with medication allergies should discuss the use of any          
nonprescription medication with their doctor," Love says.
    She adds that all three drugs have the potential to cause liver damage,   
although liver toxicity is much less common than gastric ulcers or bleeding.
    FDA is reviewing recent studies that suggest an association between use   
of all three nonprescription pain relievers and kidney disease. But the       
agency says that not enough is known yet about these possible associations    
to make any changes in current recommendations for use for healthy            
individuals.
    "I think one of the important safety issues in choosing a medication is   
it's not just whether or not you have minor pain, but what is your medical    
history on top of the minor pain," says Love. "People who have specific       
disorders--kidney disease, heart disease, bleeding problems, liver            
disorders, medication allergies--should talk to their physicians."

Acute Pain from Injury or Surgery
    When the pain becomes too much to bear, or is the result of a serious     
injury or surgery, relief requires stronger medicine and a doctor's           
prescription. One class of frequently prescribed pain relievers is            
nonsteroidal anti-inflammatory drugs, often abbreviated NSAIDs. (The three    
nonprescription pain relievers are also NSAIDs, according to Love, although   
acetaminophen is not commonly referred to by that term.)
    Prescription NSAIDs are given at higher doses than the nonprescription    
types, but the mechanism for pain relief is the same--blocking the            
production of prostaglandins. (For more information on NSAIDs, see "How to    
Take Your Medicine: Nonsteroidal Anti-Inflammatory Drugs" in the June 1990    
FDA Consumer.)
    Opiate drugs are another class of pain-relieving prescription drugs.      
Commonly prescribed opiates include morphine, codeine, hydromorphone          
(Dilaudid), and meperidine (Demerol). (In some states, some forms of codeine  
are sold without a prescription in limited amounts.) Most of these drugs are  
derived from opium, the juice of the poppy flower.
    Opiate drugs work by altering the transmission of pain messages in the    
brain and spinal cord, blocking pain messages or altering their character.
    The pain-blocking action of the opiates can be enhanced by taking         
aspirin, ibuprofen or acetaminophen at the same time as the opiate. This      
hits pain with a "double-whammy." The NSAIDS block the pain at the site of    
injury, while the opiates suppress in the brain any remaining pain.
    Unfortunately, the effect of opiates on the brain isn't limited to pain   
control. Opiates can cause drowsiness, nausea, constipation, and unpleasant   
mood changes in some people. However, sometimes simply trying a different     
opiate may be all that's needed to reduce these side effects.

Tolerance and Addiction
    Because doctors are afraid patients may become dependent on opiate        
drugs, they sometimes hold back on the amount or number of doses, even if     
this means the patient doesn't get sufficient pain relief.
    Ronald Dubner, D.D.S., chief of the Neurobiology and Anesthesiology       
Branch of the National Institute of Dental Research, says those fears are     
unfounded. But, he explains, "One needs to be very clear about making the     
distinction between tolerance and addiction." Tolerance occurs when the body  
no longer responds as well to the opiate's pain-relieving properties at the   
current dose. For example, some cancer patients with severe pain may need     
increasing amounts of morphine to maintain the same level of pain relief. 
    Addiction, on the other hand, is an overwhelming compulsion to continue   
use of the drug even when pain relief is no longer needed. While some of the  
addiction is physical, it is mainly considered a psychological dependence     
that has a detrimental effect not only on the individual, but also on         
society, because the addicted individual may have to obtain the drug          
illegally.
    Addiction is "really a red herring in the field of pain control," says    
Dubner. The fear that giving patients opiates will turn them into addicts     
craving the drugs long after the pain has ended is unfounded, says Dubner.
    "People who are truly seeking help for their pain and who are in good     
hands do not have addiction problems," he explains.
    In any case, Dubner says, it is very rare for a patient to reach a point  
where no amount of an opiate will relieve pain and that should never be used  
as a reason for not increasing the drug's dose.
    Anesthesiologist Francis Balestrieri agrees. "There's no reason to hold   
back the drug dose for people in acute pain," says Balestrieri, who is the    
director of the Woodburn Surgery Center at Fairfax Hospital in Falls Church,  
Va.
    However, FDA's Curtis Wright, M.D., warns that the pain relief from       
higher doses of opiates must be weighed against the side effects these drugs  
can cause. 
    "It's a balancing act," says Wright, who is a medical review officer for  
the agency's center for drug evaluation and research. "The amount of pain     
relief must be weighed against the effects of adverse reactions such as       
agitation, nausea, confusion, and potentially lethal respiratory depression."

Patients in Control
    Frequently, however, the doses of narcotics physicians prescribe are too  
low, not too high, and the time between doses is too long, according to a     
book by Barry Stimmel, M.D., Pain, Analgesia, and Addiction: The              
Pharmacologic Treatment of Pain. Stimmel writes that, "Analgesic medications  
should be prescribed regularly around the clock in the presence of acute      
pain. The intervals between administration should be sufficiently close       
together to avoid swings in pain levels. Both laboratory and clinical         
studies have shown that the presence of anxiety will result in an increased   
need for narcotics, thus setting up a vicious cycle whereby escalating doses  
of analgesics are needed, without adequate pain relief being obtained."
    The use of analgesics provides more benefits to the patient than just     
relieving pain. 
    "Evidence from laboratory experiments has begun to accumulate showing     
that pain can accelerate the growth of tumors and increase mortality after    
tumor challenge," writes John C. Liebeskind in an editorial in the January    
1991 issue of Pain. "It appears that the dictum 'pain does not kill,'         
sometimes invoked to justify ignoring pain complaints, may be dangerously     
wrong."
    Dubner agrees. "Pain is not a passive symptom. We consider pain, in many  
instances, an aggressive disease in itself. Therefore it becomes very, very   
critical to control pain as rapidly and as completely as possible."
    One solution to inadequate doses of pain relievers is patient-controlled  
intravenous analgesia (PCA), which is usually used in hospitals for acute     
pain following surgery. In PCA, the patient is connected to a machine called  
a PCA pump. When the patient pushes a control button, the machine delivers a  
dose of narcotic or other pain reliever intravenously. The doses are smaller  
than what would be given by injection, but because the drug goes directly     
into the bloodstream, relief can occur within seconds. A patient receiving    
traditional administration with an injection in the muscle or under the       
skin, may have to wait anywhere from 5 to 30 minutes for pain relief.
    Although the pain relief with PCA's small doses may only last for 10 to   
15 minutes, the patient can get another dose the second pain begins to        
return. Injections, on the other hand, may last up to two hours, but since    
the usual dosage schedule is three to four hours, the pain returns long       
before the nurse does.
    "PCA matches the patients' relief to their pain," says Balestrieri. "It   
also relieves patients of the worry over their pain relief in the majority    
of cases."
    It also helps patients deal with the side effects opiates can cause,      
says FDA's Wright.
    "A substantial portion of patients don't want complete pain relief,"      
says Wright. "They want as much pain relief as they can get without bad side  
effects."
    Wright says that when the first studies were done on the effectiveness    
of PCA, "we thought that the pain scores [the patients gave] would be zero."  
(Patients generally rated pain on a four-point scale with four being the      
greatest amount of pain and zero, no pain.)
    "What we found was that patients didn't titrate down to zero, but         
instead brought the pain down to one or two," he says. 
    The undesirable side effects of narcotics can be avoided completely with  
another form of continuous administration--epidural therapy. Epidurals,       
which inject the narcotics into the membrane surrounding the spinal cord,     
have been used for many years to block the pain of labor. Now this is being   
adapted to control pain after some major surgery, especially abdominal.
    Drugs injected into the epidural space don't travel to the brain like     
other types of injections, explains Sherry Fisher, R.N., pain management      
coordinator at Fairfax Hospital. Therefore, complications such as nausea and  
respiratory depression don't occur.
    With epidurals "patients can talk to me, take deep breaths, cough, and    
even be up and walking around, sometimes 24 hours after surgery," says        
Fisher. Normally, after the type of major surgery that requires the kind of   
pain control epidural therapy provides, "the patient would still be on a      
ventilator after 24 hours," she says.
    However, epidurals aren't effective for every type of pain. Besides pain  
from abdominal surgeries, epidurals are best used for pain following major    
chest and urologic surgery, according to Fisher.
    No matter what the form of administration, "I don't think people should   
be exposed to any more pain than they're willing to tolerate," says Dubner.

Chronic Pain
    Unfortunately, "when it comes to chronic pain, there are situations       
where pain cannot be controlled as well with the approaches that are          
available to us today," says Dubner.
    Opiate drugs are usually avoided in chronic pain management because of    
the potential for tolerance.
    Some types of chronic pain that are difficult to control include:
- pain from nerve damage caused by diabetes or shingles
- lower back pain that continues long after the initial injury has healed
- arthritis
- migraine and other chronic headaches.
    There is some hope though. Tricyclic antidepressants, especially          
amitriptyline, have been found to relieve pain in patients with nerve         
damage. These drugs aid the body's own defenses by trapping serotonin, a      
pain-blocking chemical, at its point of production in the nerve endings in    
the dorsal horn of the spinal cord (see accompanying diagram). An excess of   
serotonin builds up and suppresses pain signals longer than usual.
    Although FDA has not approved tricyclic antidepressants for pain          
control, these drugs are gaining wide acceptance for this purpose. (The       
practice of medicine may include the prescribing of approved drugs for        
unapproved uses supported by research and not otherwise contraindicated.)
    Treatment of chronic and migraine headache pain may include two drugs     
approved for heart problems--calcium channel blockers and beta blockers.
    Treatment for mild arthritis pain, on the other hand, often begins with   
aspirin. If the patient can't tolerate aspirin, ibuprofen is a reasonable     
substitute, says Love. She warns, however, that even though people can buy    
aspirin and ibuprofen without a prescription, the doses required to treat     
arthritis pain are too high to be taken without a physician's care.
    "The treatment of chronic arthritis, regardless of severity, requires an  
adequate diagnosis and possible use of many different types of medications,   
physical therapy, or surgery," says Love.

TENS
    Another potential source of relief for chronic pain is transcutaneous     
electrical nerve stimulation (TENS). Through the use of the TENS device--a    
battery-powered generator that could be mistaken for a Walkman portable       
radio or a beeper--electrical impulses are transmitted to the site of pain    
through electrodes placed on the skin.
    With the most common course of treatment, the physician or physical       
therapist sets the TENS device to deliver 80 to 100 impulses a second for 45  
minutes, three times a day.
    But there are a wide variety of parameter ranges, and what works for one  
person may have no effect on another. Determining the most effective          
settings "is a real art," says Stephen M. Hinckley, a physiologist with       
FDA's Center for Devices and Radiological Health.
    Pain can be very subjective, explains Hinckley. Two people whose pain is  
caused by the same problem may need very different settings to achieve        
relief. 
    If a patient doesn't require hospital care, the patient can use the TENS  
device, preset to the proper level, at home. The device does not interfere    
with most normal activities.
    A study published in the New England Journal of Medicine in June 1990     
questioned the effectiveness of TENS. The study concluded "that for patients  
with chronic low back pain, treatment with TENS is no more effective than     
treatment with a placebo, and TENS adds no apparent benefit to that of        
exercise alone."
    But, because a number of previous studies support the use of TENS, FDA    
still considers TENS to be effective for pain relief for some people. 
    Although it isn't clear why TENS works, there are two plausible           
theories, according to the Harvard Medical School Health Letter. The first    
holds that nerves can easily carry only one message at a time. The            
electrical pulses from TENS overload the nerves, and the pain message shuts   
down. A second theory hypothesizes that the electrical pulses stimulate the   
body to release its own painkilling molecules, called endorphins, into the    
fluid bathing the spinal cord.
    Pain researchers are studying how to stimulate production of the brain's  
own opiates, such as endorphins, enkephalins and dynorphins, since they may   
act as natural painkillers, according to NIH's Dubner.
    "There are clear indications that stimulation in certain parts of the     
brain can be helpful in some patients," he says.

Focus on Life
    Sometimes, though, none of these therapies will completely relieve the    
pain for chronic sufferers. They don't have to give up hope, though. For      
many in chronic pain, behavior modification techniques such as biofeedback,   
meditation and relaxation training may offer some relief. These treatment     
approaches are designed to alter a patient's reactions and behavior in        
response to pain.
    "They learn that they can deal with their pain effectively if they focus  
on improving their quality of life instead of focusing on their pain," says   
Dubner.
    Seymour Rubin, 67, who has suffered with chronic back pain for 40 years,  
agrees. "If I focus on the pain, it just gets worse," he says. Instead,       
Rubin keeps busy with walking, reading, and running errands with his wife.
    "Singing helps, talking helps," adds Rubin. "And I've just learned to     
accept the fact that I have pain." n

Dori Stehlin is a staff writer for FDA Consumer.
How You Know That You Stubbed Your Toe

1. Nociceptors are specialized nerve endings in the skin and other            
peripheral tissues that respond exclusively to tissue-damaging stimuli.       
Prostaglandins sensitize these nerve endings, and the pain message starts on  
its way to the brain. Aspirin and ibuprofen and, to a lesser extent,          
acetaminophen can block prostaglandin production at this point.
2. Pain travels along special nerve fibers to the part of the spinal cord     
called the dorsal horn. 
3. Tricyclic antidepressants work here by enhancing the effects of the        
body's own natural painkillers.
4. From the dorsal horn, the pain ascends to the thalamus and then to the     
cerebral cortex. Opiates cause the brain to suppress pain messages before     
they leave the dorsal horn. 

--D.S.
Clinical Studies
    The Pain Research Clinic at the National Institutes of Health has         
ongoing studies in the following areas:
- wisdom tooth extraction
- painful diabetic neuropathies
- causalgic-type pains, including reflex sympathetic dystrophy
- oral-facial pain, including temporomandibular disorders.
    To find out how to become a patient in these studies, write:
Jean Itkin
National Institute of Dental Research
National Institutes of Health
Building 10, Room 3C407
Bethesda, Md. 20892
Telephone: (301) 496-0394