There are three broad categories of analgesic drugs (Portenoy 2000, 2002).
Nonopioid Analgesics
The nonopioid analgesics include acetaminophen (also called paracetamol),
dipyrone (not available in the U.S.) and the nonsteroidal anti-inflammatory
drugs (known as the NSAIDs). The NSAIDs are nonspecific analgesics and
can potentially be used for any type of acute or chronic pain. Because
they are both analgesic and anti-inflammatory, however, they may be
particularly useful for pain related to joint problems and other
musculoskeletal disorders (Wallenstein, 2002).
The NSAIDs are a very diverse group of drugs. They all inhibit
an enzyme called "cyclo-oxygenase" (COX). COX exists in many
tissues and inhibition of this enzyme reduces the amount of
chemicals known as "prostaglandins" in these sites. Prostaglandins
have many roles, including the production of inflammation. Inhibition
of COX by a NSAID, therefore, may reduce pain and inflammation.
There are at least two forms of COX. COX-1 is more involved in the
normal functioning of organs like the stomach, while COX-2 is more
involved when inflammation starts to occur. Most of the NSAIDs
inhibit both COX-1 and COX-2. Recently, a few NSAIDs that selectively
inhibit COX-2 have become available. These "COX-2 selective inhibitors"
reduce the risks of some of the side effects associated with NSAID therapy.
The NSAIDs that inhibit both COX-1 and COX-2 include:
- Salicylates, like aspirin, diflunisal, choline magnesium
trisalicylate, and salsalate
- Proprionic acids, like ibuprofen (Motrin ™), naproxen (Naprosyn
™), fenoprofen , ketoprofen , flurbiprofen and oxaprozin
- Acetic acids, like indomethacin (Indocin ™), tolmetin, sulindac , diclofenac
, ketorolac , and etodolac
- Oxicams, like piroxicam (Feldene ™)
- Naphthlyalkanones, like nabumetone (Relafen ™)
- Fenamates, like mefenamic acid and meclofenamic acid
- Pyrazoles, like phenylbutazone
The COX-2 selective inhibitors include
- celecoxib (Celebrex ™)
- rofecoxib (Vioxx™)
- valdecoxib (Bextra™)
- meloxicam (Mobic™) when used at a lower dose.
There is large variation in the way patients respond to the NSAIDs. An individual
may respond very well to some of these drugs and not at all to others. Some
may be associated with side effects, whereas others are very well tolerated.
The usual doses prescribed may be optimal in one case, but either too high
or too low for another. Given all this variation, physicians often must
try several of these drugs to identify the best one. Although usually a
conventional dose is prescribed, the physician may decide to start with
a relatively low dose and then increase the dose slowly to find the correct
dose for the individual.
Side effects are relatively common with the NSAIDs. Gastrointestinal (GI)
symptoms occur in about 10% of patients treated with the nonselective COX-1
and COX-2 NSAIDS, and ulcers occur in about 2%. The factors that have been
associated with an increased risk of ulcers include advanced age, higher
NSAID dose, administration of a corticosteroid drug along with the NSAID,
a history of either ulcer disease or previous GI complications from NSAIDs,
and probably heavy alcohol or cigarette use. Nausea and abdominal pain are
poor predictors of serious GI toxicity and most patients who develop ulcers
actually have no symptoms at all before the ulcer appears.
The risk of GI symptoms and ulcers also varies from drug to drug. In the
large group of nonselective COX-1 and COX-2 NSAIDs, some are relatively
less likely to cause these problems compared to the others. More importantly,
the newer COX-2 selective drugs have been shown to reduce the risk of both
GI symptoms and ulcer formation. The availability of these selective COX-2
selective drugs is widely considered to be an important advance for this
reason. Still, there have not been enough scientific studies performed to
know for sure whether the added cost of these drugs is balanced by their
possible advantages. Most experts now feel that these drugs should be considered
first-line at least for those patients who have a relatively increased risk
of GI toxicity. The largest population for which this guideline would apply
is the elderly.
The risk of ulcer also can be reduced by administering a so-called "gastroprotective"
therapy along with the NSAID. The protective drugs include misoprostol;
the so-called proton pump inhibitors, such as omeprazole and lansoprazole;
and possibly higher doses of the H2 blockers, such as famotidine. Antacids
can reduce symptoms but do not decrease ulcer risk.
All NSAIDs, including the selective COX-2 drugs, can cause renal toxicity
and must be used cautiously in patients who have known kidney disease or
may have kidney disease because of advanced age or a disease. The renal
problems range from just swelling from fluid retention all the way to renal
failure. Patients who receive these drugs should have kidney function monitored
from time to time.
The nonselective COX-1 and COX-2 NSAIDs inhibit the effects of platelets,
which are cells in the blood stream that play an important role in clotting.
Patients who take these drugs, therefore, have a relatively higher risk
of bleeding. The selective COX-2 drugs have no effect on platelets.
Adjuvant Analgesics
The so-called adjuvant analgesics are defined as drugs that are on the market
for indications other than pain but may be analgesic in selected circumstances.
They include a very large number of drugs in numerous drug classes (Thiessen,
2003).
Antidepressants. Most antidepressant medications are
analgesics, and can relieve chronic pain even if the patient has no coexisting
depression. The specific anti-depressant effects are also important—alleviating
chronic depression is important in helping patients deal more effectively
with pain. Although the overall response to these drugs is mixed (various
types of studies suggest that they work in fewer than 50% of patients),
they may be considered to be nonspecific analgesics, potentially capable
of relieving all types of pain. There are different classes of antidepressants,
which probably vary in their analgesic ability. Evidence is best that
the “tricyclic” antidepressants, such as amitriptyline (Elavil™),
imipramine, doxepin , clomipramine , desipramine and nortriptyline , are
analgesics. There is evidence that at least some of the so-called serotonin-selective
reuptake inhibitors (SSRIs), like paroxetine (Paxil™) and citalopram
(Celexa™), and the serotonin and norepinephrine reuptake inhibitors
(SNRIs), such as venlafaxine (Effexor™), are also pain relievers.
Several other antidepressants, such as bupropion (Wellbutrin™) and
maprotiline (Ludiomil™), also have been studied and have been shown
to have analgesic effects.
Anticonvulsants. Many anticonvulsants have been proven
to relieve neuropathic pain, such as painful diabetic neuropathy, postherpetic
neuralgia, trigeminal neuralgia and other conditions. The most commonly
used drug at the present time is gabapentin (Neurontin™). Many other
drugs may be tried, however, including phenytoin , carbamazepine, clonazepam,
oxcarbazepine, lamotrigine, tiagabine, topiramate, and levetiracetam.
Individual patients may have great variability in their response to the
different drugs.
Local anesthetic drugs. When injected close to a nerve,
a local anesthetic produces regional anesthesia, numbness in the distribution
of the nerve. When taken orally or intravenously, a local anesthetic drug
can provide pain relief. These drugs are used to treat neuropathic pain.
The oral agents include mexiletine, tocainide and flecainide. Intravenous
or subcutaneous infusion of lidocaine is used for the same purpose.
Alpha-2 adrenergic agonists. Drugs such as clonidine
(on the market for high blood pressure) and tizanidine (on the market
to treat spasticity) are nonspecific analgesics. Although the overall
response rate appears to be only fair, some patients clearly benefit.
Potentially, any type of pain may be treated with these drugs.
GABA agonists. Baclofen is a drug that interacts with
the brain receptor for GABA, an important neurotransmitter. Baclofen has
been used for many years as a treatment for neuropathic pain. It has been
specifically studied in trigeminal neuralgia.
NMDA receptor antagonists. Recent studies have shown
that a specific receptor called the n-methyl-D-aspartate (NMDA) receptor
is very important in the development of neuropathic pain. There are several
drugs that block this receptor, including dextromethorphan, amantadine,
ketamine and memantine (not available in the U.S.). All these drugs are
used now to treat neuropathic pain.
Corticosteroids. Corticosteroid drugs, such as prednisone,
methylprednisolone, and dexamethasone, have the same effects as hormones
produced by the body's adrenal glands. They are used to treat inflammatory
diseases such as rheumatoid arthritis and are also used as adjuvant analgesics
in some conditions. Because the adverse effects from these drugs worsen
with the duration of treatment, physicians often try to use them temporarily.
Some patients with challenging problems are given long-term therapy.
Muscle relaxants. The so-called muscle relaxant drugs
do not actually relax skeletal muscle but are on the market as pain relievers
for musculoskeletal pain problems, such as lumbar strain. These drugs
include metaxalone, carisoprodol, methocarbamol and others. Usually, these
drugs are used for a short period of time, but occasional patients appear
to benefit from longer therapy.
Topical agents. In some cases, drugs applied to the skin
can be analgesic. Local anesthetics are commonly used in this way. A patch
containing lidocaine is approved in the U.S. for the treatment of postherpetic
neuralgia and is now being used for a variety of other pain problems.
High concentration lidocaine and a mixture of lidocaine and prilocaine,
known as EMLA, are also used for this purpose. Studies have shown that
topical capsaicin, the active ingredient in chili peppers, appears to
be able to relieve various types of pain, and other studies have suggested
analgesic effects from topical antidepressants, such as doxepin. Topical
NSAIDs are available in many countries and may be useful for musculoskeletal
pain and there is some early information suggesting that topically applied
opioid drugs may also be beneficial. Numerous other drugs are sometimes
compounded into creams and gels, and tried in difficult pain situations,
but there is no evidence at this point that they help.
Opioid Analgesics
The most effective analgesics by far are the opioid analgesics (Ellison,
1998). The opioids include all drugs that interact with opioid receptors
in the nervous system. These receptors are the sites of action for the
endorphins, compounds that already exist in the body and are chemically
related to the opioid drugs that are prescribed for pain.
The opioids consist of several classes. The so-called antagonists have
no analgesic effect and are used to block the effects of opioid drugs.
In the clinical setting, antagonist drugs are used to reverse opioid toxicity,
typically from overdose. They are also being investigated as a treatment
for opioid-induced constipation. One antagonist drug, naltrexone, is also
used to treat alcohol addiction.
The antagonist drugs include:
- Naloxone (Narcan™)
- Naltrexone (Trexan™)
- Nalmafene (Revex™)
The so-called agonist-antagonist drugs have a relationship to the opioid
receptors that includes activation and blockade. Some of these drugs activate
one type of opioid receptor, known as the kappa receptor, while blocking
another, the mu receptor. Others just interact with the mu receptor and
activate it until the dose is increased to a certain point, at which the
activation effect plateaus and then drops. These drugs are sometimes used
to treat acute pain or headache. One of these drugs, buprenorphine, is also
being used to treat opioid addiction.
The agonist-antagonist class includes:
- Buprenorphine (Buprenex™)
- Butorphanol (Stadol™)
- Nalbuphine (Nubain™)
- Dezocine (Dalgan™)
The agonist-antagonist opioid class have several disadvantages when compared
to the major class of opioid analgesics, the pure mu agonists. All of these
drugs have a ceiling effect, meaning that there is a dose above which higher
doses produce no additional pain relief. None of them can be given to patients
who are already receiving another opioid because they can, in some of these
circumstances, produce withdrawal. Finally, some of the agonist-antagonist
drugs tend to produce more confusion than the pure mu agonist class. In
short, these drugs can be used to treat acute or chronic pain but there
are no definite advantages in most patients when compared to the pure mu
agonists and there are some potential disadvantages to consider.
The pure mu agonist class include a large number of specific drugs, some
of which are available in combination with aspirin, acetaminophen or ibuprofen,
and some of which are available in extended-release formulations. Historically,
these drugs have been the mainstay approach for the short-term management
of acute severe pain and for the long-term management of moderate-to-severe
pain related to cancer and other life-threatening illnesses. During the
past fifteen years, there has been an evolving acceptance of long-term treatment
for selected patients with severe chronic pain of other types.
The pure mu agonists include:
- Short-acting oral drugs that may be combined with a nonopioid drug
and are typically prescribed for acute pain in the outpatient setting.
This group includes codeine, hydrocodone, oxycodone, and others.
- Short-acting drugs that may be given intravenously, subcutaneously
or intramuscularly and are usually administered for acute pain in the
inpatient setting. This group includes morphine, meperidine, hydromorphone,
fentanyl, and others.
- Long-acting drugs that are usually administered in the outpatient
setting for the long-term management of chronic pain. This group includes
extended-release oral morphine, extended-release oral oxycodone, extended-release
oral hydromorphone, extended-release transdermal (via a skin patch)
fentanyl, and methadone.
All the pure mu agonist drugs share some characteristics. First, there is
no ceiling dose. In most cases, pain is relieved more and more as the dose
is increased, until side effects limit therapy. Patients who develop intolerable
side effects without achieving satisfactory analgesia are called “poorly
responsive” to the specific drug.
All of the pure mu agonist drugs have the same potential for side effects,
but individual patients vary a great deal in the specific side effects experienced
and the pain relief that will occur before side effects become a problem.
This variability from patient to patient means that the responsiveness of
individuals to the various opioid drugs varies. For example, some patients
have better effects from morphine than oxycodone, and some are just the
opposite.
The side effects associated with the opioid drugs include the following:
- Constipation. This is very common and is often a persistent problem.
- Nausea. This may occur at the start of therapy. It usually passes
after a short time.
- Sleepiness, fatigue, dizziness and mental clouding. These are common
at the start of therapy and usually pass after a short while.
- Itch
- Urinary retention
- Dry mouth
- Sexual dysfunction
Opioid drugs can cause breathing to slow and, in overdose, can be lethal.
Breathing problems of this type are very rare when these drugs are administered
in an appropriate way.
Among the most feared effects of the opioid drugs are those related to the
problem of chemical dependency. There is a great deal of misconception about
this issue. Opioids, like a number of other drug classes, have the potential
to be abused or diverted into the illicit marketplace. Addiction is a concern.
There is often confusion about the meaning of the word “addiction”
and how much risk there is. To assess this, the first step is to define
the problems correctly.
Addiction is a disease that has a genetic aspect (a biological part) and
a psychosocial aspect and is diagnosed by the development of drug-related
behaviors consistent with 1) compulsive use of a drug, 2) loss of control
over the drug, 3) craving for the drug, and 4) continued use of the drug
despite harm to the user or others.
Physical dependence means that a person will probably have withdrawal if
the drug is stopped or an antagonist drug is given. This physiological process,
which occurs with many other types of drugs, is not the same as addiction
and should never be called addiction. In practice, withdrawal typically
does not occur if the drug is not stopped suddenly, and for this reason,
physical dependence is not a major concern.
Tolerance is another physiological process defined
by the gradual loss of effect over time as the body gets used to the drug.
Tolerance to nausea and mental clouding occur commonly. Tolerance to pain
relief is not a major problem in the clinical setting.
Abuse is a term that means that the drug is not being used in a responsible
way. Either a drug is being used outside of social norms, or in a way that
is contrary to how it was prescribed.
Aberrant drug-related behavior is the term applied to the use of
drugs in a manner that suggests some type of problem. It could be abuse
or addiction, or it could be a lack of understanding or desperation that
comes from uncontrolled pain. Clinicians should always monitor patients
for the development of these problems, determine the cause, and then act
accordingly.
Opioids could potentially be used, either short-term or long-term, for any
severe pain. Some of the key principles that apply to these drugs include
the following:
Selecting the therapy. Opioids are typically first-line
if the pain is severe and is expected to be short-lived, like post-surgical
pain, and if the pain is associated with a progressive incurable illness.
In other types of chronic pain, a decision to try an opioid should be based
on a careful evaluation by the clinician. This evaluation should try to
answer several questions: Is the pain severe enough to warrant this therapy?
Are there other therapies just as safe as the opioids that might work as
well or better? Is the use of an opioid complicated by some medical problem
that makes them relatively less safe? Is this patient likely to be responsible
with these drugs, or is there some indication that drug-taking behaviors
might become a problem?
Individualize the therapy. For short-term therapy, a short-acting
drug is usually selected. For longer term therapy, a long-acting drug is
preferred. Whatever drug is selected, the key to successful therapy is gradual
adjustment of the dose until a favorable balance between pain relief and
side effects is attained. If this favorable balance is not possible with
one drug, a switch to another opioid might be considered.
Treat side effects. Many patients will need treatment for
constipation during therapy. Some will need a medicine for nausea. During
long-term therapy, some physicians will administer a stimulant drug if the
pain control is good but therapy is compromised by sleepiness, fatigue or
mental clouding.
Consider other therapies. Patients with chronic pain often
do best when one or more pain-relieving drugs are combined with other therapies,
including rehabilitative approaches, psychological therapies, injections,
or CAM approaches.
Follow the appropriate outcomes. There are four types of
outcomes that should be monitored by the physician prescribing an opioid
therapy: 1) pain relief, 2) side effects, 3) physical and psychosocial functioning,
and 4) the occurrence of any aberrant drug-related behaviors. Patients should
be made aware by their prescribers that there are a wide variety of side
effects possible with the use of these medications. It is important that
patients talk with their providers about any changes they have noticed in
any area of their lives since beginning a new treatment regimen. Patients
can help by being prepared to discuss these outcomes with the prescriber.
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