Physical Dependence, Addiction, and Tolerance
Opioid Treatment Guidelines
The most effective analgesics by far are the opioid analgesics. 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:
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:
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
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
||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
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.
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.
Opioids can potentially be used, either short-term or long-term, for any
severe pain. They are widely accepted as the preferred treatment for acute
pain and chronic pain associated with cancer. Although the use of opioid
drugs on a long-term basis to treat chronic noncancer pain is still controversial,
pain specialists now agree that selected patients can benefit. When used
appropriately, these patients can experience sustained pain relief with
tolerable side effects and little risk of ever developing addiction. As
pain relief improves, patients may be able to function better and experience
a much improved quality of life.
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:
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.
- pain relief,
- side effects,
- physical and psychosocial functioning, and
- the occurrence of any aberrant drug-related behaviors.
As more doctors begin to consider a trial of opioid therapy for patients
with chronic noncancer pain, the need to eliminate the stigma, the myths,
and the misconceptions that surround these drugs is a priority. Pain specialists
have been working toward this goal. The following are some key points
about opioid therapy:
||Many people confuse physical dependence,
which is the occurrence of withdrawal when the drug is stopped,
with addiction. Withdrawal is a physical phenomenon that means that
the body has adapted to the drug in such a way that a "rebound"
occurs when the drug is suddenly stopped. The kind of symptoms that
occur include rapid pulse, sweating, nausea and vomiting, diarrhea,
runny nose, "gooseflesh," and anxiety. All people who
take opioids for a period of time can potentially have this withdrawal
syndrome if the drug is stopped or the dose is suddenly lowered.
This is not a problem as long as it is prevented by avoiding sudden
reductions in the dose.
Physical dependence is entirely different from addiction. Addiction is
defined by a loss of control over the drug, compulsive use of the drug,
and continued use of the drug even if it is harming the person or others.
People who become addicted often deny that they have a problem, even as
they desperately try to maintain the supply of the drug.
Addiction is a "biopsychosocial"
disease. This means that most people who become addicted to drugs
are probably predisposed (it is in the genes) but only develop the
problem if they have access to the drug and take it at a time and
in a way that leaves them vulnerable. A very large experience in
the treatment of patients with chronic pain indicates that the risk
of addiction among people with no prior history of substance abuse
who are given an opioid for pain is very low. The history of substance
abuse doesn't mean that a patient should never get an opioid for
pain, but does suggest that the doctor must be very cautious when
prescribing and monitoring this therapy.
People with chronic pain should understand the difference between physical
dependence and addiction. Unreasonable fears about addiction should not
be the reason that doctors refuse this therapy or patients refuse to take
||Tolerance to opioid drugs occurs but is seldom a clinical problem.
Tolerance means that taking the drug
changes the body in such a way that the drug loses its effect over
time. If the effect that is lost is a side effect, like sleepiness,
tolerance is a good thing. If the effect is pain relief, tolerance
is a problem. Fortunately, a very large experience indicates that
most patients can reach a favorable balance between pain relief
and side effects then stabilize at this dose for a long period of
time. If doses need to be increased because pain returns, it is
more commonly due to worsening of the painful disease than it is
||Although opioids can make people sleepy and cloud their thinking,
this side effect is usually temporary and long-term therapy is usually
associated with normal thinking. Many people fear that taking an
opioid will cause them to become "a zombie," unable to
function even if the pain is relieved. Fortunately, this is not
the case. Most patients can take these drugs for a long period of
time and be mentally normal. Patients who have been stabilized on
opioid therapy and are clearheaded can drive, work, and do whatever
else is necessary.
||Opioid drugs are not a cure-all. Although pain specialists now
believe that many patients can benefit from this therapy, they also
recognize that some patients do poorly. Some patients experience
sleepiness or mental clouding that never clears, and still others
develop persistent nausea or severe constipation. Some patients
actually do not function well when treated with these drugs. Finally,
some cannot be responsible drug takers; rarely, a true addiction
For all these reasons, chronic opioid therapy is generally not a
first-line treatment for patients with persistent pain. Each patient
who is a possible candidate should be evaluated by a professional
who is knowledgeable about the use of this therapy.
||Patients who receive a trial of an opioid drug should expect to
be carefully monitored by their physicians. Any patient given opioid
drugs to treat pain should follow the doctor's prescription exactly.
Patients should never increase the dose on their own. They should
never go to another physician to get prescriptions and should always
be completely honest in reporting the effects produced by the drug.
The physician will inquire about pain relief; side effects; the
ability to function physically, psychologically and socially; and
the occurrence of any behavior that suggests problems in controlling
the medication. For some patients, very intensive monitoring is
appropriate; for others, monitoring can be less intensive.
Some doctors will want the patient to agree to a contract that describes
the patient's responsibilities when taking the drug. Some physicians
will even want to monitor the patient's urine to make sure that
the patient is taking only the drugs that should be taken. A physician
may want these things to feel secure in the knowledge that the patient
is appropriately using the drug. When the physician is able to have
this security, he or she is free to act in the patient's best interests.
A good relationship between the physician and patient is needed
for long term opioid therapy to be successful.
||The drugs that are now used to treat chronic pain include morphine,
hydromorphone, oxycodone, fentanyl, methadone and others. Some opioids,
like codeine and hydrocodone, are usually prescribed in combination
with acetaminophen or aspirin. Although the latter drugs are sometimes
used for chronic pain, long-acting drugs are generally preferred.
These long-acting drugs can be taken twice a day, once a day or,
in the case of the fentanyl, by patch.
Although some people believe that opioid drugs are only appropriate
for certain kinds of pain, doctors are unable to accurately predict
which pain problems will not respond.
Each opioid produces a different range of effects in each individual.
The same person may get too sleepy from morphine but experience
very little sleepiness from oxycodone, or vice versa. For this reason,
many pain specialists are now suggesting that patients with chronic
noncancer pain be given an opportunity to try different commercially
available opioid drugs in order to find the drug that produces the
most favorable balance between pain relief and side effects.
||Regardless of the opioid, the dose often has to be adjusted to
get the best effect. Patients should understand that adjustment
of the dose and the use of other medicines, like laxatives, to treat
side effects are a common part of therapy.
View recent treatment guidelines for the use of opioid therapy in chronic noncancer pain:
Opioid Treatment Guidelines (.pdf) - The Journal of Pain, Vol
10, No 2 (February), 2009: pp 113-130
For more information about chemical dependency, see our
Pain and Chemical