I
Review Article
Opioids for Chronic Nonterminal Pain
Jane C. Ballantyne,
MD, FRCA
Abstract: This article first reviews the evidence for and against
chronic opioid therapy. Evidence supporting the opioid responsiveness of chronic pain, including neuropathic pain, includes multiple
randomized trials conducted over months (up to 8 months). Observational studies are conducted for longer, and many also support
opioid analgesic efficacy. Concerns have arisen about loss of efficacy with prolonged use, possibly related to tolerance or opioidinduced hyperalgesia. Mechanisms of tolerance and opioid-induced
hyperalgesia are explored. Evidence on other important outcomes
such as improvement in function and quality of life is mixed, and is
less convincing than evidence supporting analgesic efficacy. It is
clear from current evidence that many patients abandon chronic
opioid therapy because ofthe unacceptability of side effects. There
are also concerns about toxicity, especially when opioids are used in
high doses for prolonged periods, related to hormonal and immune
function.
The issue of addiction during opioid treatment of chronic pain
is also explored. Addiction issues present many complex questions
that have not been satisfactorily answered, Opioid treatment of pain
has been, and remains, severely hampered because of actual and
legal constraints related to addiction risk. Pain advocacy has focused
on placing addiction risk into context so that addiction fears do not
compromise effective treatment of pain. On the other hand, denying
addiction risk during opioid treatment of chronic pain has not been
helpful in terms of providing physicians with the tools needed for
safe chronic opioid therapy. Here, a structured goal-directed approach to chronic opioid treatment is suggested; this aims to select
and monitor patients carefully, and wean therapy if treatment goals
are not reached.
Chronic opioid therapy for pain has not been a universal success since it was re-established during the last two decades of the
twentieth century. It is now realized that the therapy is not as effective or as free from addiction risk as was once thought. Knowing
this, many ethical dilemmas arise, especially in relation to patients'
right to treatment competing with physicians' need to offer the treatment selectively. In the future, we must learn how to select patients
for this therapy who are likely to achieve improvement in pain,
function and quality of life without interference from addiction.
Efforts will also be made in the laboratory to identify opioids
with lower abuse potential.
Key Words: pain, chronic disease, opioids, drug tolerance, addiction, neuroendocrine effects
C
hanges arising during the twentieth century profotmdly altered the way opioids were used for the treatment of pain.
These included the introduction in the first decade of drug regulations attempting to control the proliferation of addictive drugs;
the subsequent difficulties of convincing patients and physicians
that opioids could be used for the treatment of pain without fear
of censure; the scientific breakthroughs of the early 1970s confirming the existence of endogenous opioid systems and their
role in analgesia and addiction''^; the realization that pain is a
destructive disease process that should be treated; the acceptance
that opioids are indispensable for the treatment of acute and
terminal cancer pain; and finally, during the last two decades of
the century, the extension of opioid treatment to patients with
Key Points
•
•
•
From the Division of Pain Medicine, Massachusetts General Hospital Department of Anesthesia and Critical Care and the Department of Anesthesia, Harvard Medical School, Boston, MA.
Reprint requests to Jane C. Ballantyne, MD, FRCA, Chief, Massachusetts
General Hospital Pain Center, 15 Parkman Street, WACC 333, Boston,
MA 02114. Email: [email protected]
Accepted March 23, 2006.
Copyright © 2006 hy The Southem Medical Association
003 8-4348/0 - 2000/9900-1245
Southern Medicat Journat • Volume 99, Number 11, November 2006
•
•
Opioid treatment was extended to patients with longterm (chronic) pain after it had been firmly established as safe and effective for acute and cancer pain.
Two decades of experience with this therapy have
taught that there are reasons for caution related to loss
of efficacy over time, toxicity and higher than expected addiction risks,
Most authorities agree that improved quality of life—
regardless of whether this occurs in the presence of
addiction—is a satisfactory outcome of chronic opioid
therapy for pain.
A cautious and selective treatment approach is recommended.
Future efforts will be focused on developing screening tools to help identify patients at risk before and
during treatment.
1245
Ballarityne • Opioids for Chronic Nonterminal Pain
chronic, nonterminal pain,* Physicians must now accept that it is
not considered legal, ethical or good medical practice to withhold opioids irom patients whose lives could be improved with
treatment. Yet chronic opioid management is not suitable for
every patient; there are considerable risks involved, and the treatment is not universally effective. This article presents current
evidence on the benefits and risks of long-term opioid therapy,
suggests a structured approach to chronic opioid management
for pain, and discusses some of the issues surrounding opioid
treatment of chronic pain that make achieving a balance and
satisfying the needs of patients a veritable challenge.
is much more difficult to assess, not least because the
factors that influence analgesic effect over time are complex. These factors include the development of tolerance,
and the development of opioid-induced hyperalgesia and
psychological factors such as changes in the placebo component. Reports in the literature comprise case and case
series reports, surveys^'*"''^ and open-label follow-up studies in association with some RCTs.^''^"'^'^^'^^'^^
These report treatment durations of up to 6 years. The
general finding is that patients attain satisfactory analgesia
using moderate nonescalating doses (up to 195 mg morphine
equivalence per day), often accompanied by an improvement
in function, and minimal risk of addiction. It must be remembered, though, that these studies are anecdotal, comprising
Evaluating Chronic Opioid Therapy
reports written by experts who likely carried out the treatment
Analgesic Efficacy
with unusual care. This inherent bias is particularly relevant
to chronic opioid therapy, which requires considerable dediAdding to concerns about addiction during opioid treatcation, patience and caution to be successful,'^^
ment of chronic pain, there has been a traditionally held view
that chronic pain states such as neuropathic pain are not senA slightly different picture emerges from recently published
sitive to opioids. Yet clinical observation suggests that chronic
open-label follow-up studies, which suggests that the failure rate
pain states are, in fact, relieved by opioid treatment. It was
of chronic opioid therapy may be higher than was previously
this uncertainty about the opioid sensitivity of chronic pain
thought. The authors of a 2004 meta-analysis of chronic opioid
that prompted several investigators to conduct randomized
therapy systematically assessed available follow-up studies and
controlled trials (RCTs) assessfound a 56% drop-out rate,^*
ing the analgesic efficacy of
Although these reviewers were
opioids for chronic pain states Opioid-induced hyperalgesia is now
unable to distinguish drop out
such as the arthritides and neu- understood to coexist with opioid
due to inadequate analgesia
ropathic pain. In some trials, a analgesia, with analgesia being
from drop out due to unacceptsingle IV treatment was predominant in most circumstances.
able side effects, the high dropused,''"^ in others, oral treatout rate does seem at odds with
ment was used over longer pethe high success rates reported
riods of up to 32 weeks. Table 1 summarizes the controlled
in observational studies, Ftirther study is needed to determine
trials of oral treatment.^^'^'^ In both types of trials, chronic
how many, and particularly which, patients respond well to longpain conditions are seen to be sensitive to opioids. In fact,
term opioid therapy in terms of analgesic efficacy.
opioids provide superior analgesic efficacy when compared
As more patients are treated with opioids,^^'^' more patients
both to placebo and to established treatments (usually nonpresent to physicians with severe pain despite opioid treatment steroidal anti-infiammatory drugs) for a number of chronic
sometimes despite high-dose opioid treatment,'*"'*' Reports of
pain conditions. In the case of neuropathic pain specifically,
difficulty controlling acute pain when it arises in opioidthe dose-response curve is shifted to the right (a higher dose
treated or opioid-using patients, also suggest that something
is needed), but the opioid sensitivity of neuropathic pain states
is interfering with analgesic efficacy,'*^ Several authors have
is confirmed,'^''^-"^-^''^^
reported that weaning some patients off opioids results in an
While the short-term efficacy of opioids for treating
improved sense of well being and no change in pain — someseveral chronic pain conditions now seems certain, the
times pain may even improve.'*''"'''' It seems that in these
information from controlled trials is limited by their being
patients at least, there is virtually no analgesic effect, since
conducted only for short periods. This limitation occurs
treatment discontinuation results in no change in pain. Why
largely because of the impracticability of conducting conshould pain improve or remain the same upon discontinuing
trolled trials over prolonged periods. The question of
opioid treatment? Here, advances in basic science have helped
whether analgesic efficacy and other benefits of chronic
us understand mechanisms that could account for analgesic
opioid therapy can be maintained over years rather than
failure, Opioid-induced hyperalgesia, for example, is now
months remains unanswered. Long-term analgesic efficacy
understood to coexist with opioid analgesia, with analgesia
being predominant in most circumstances, A^-methyl-Daspartate (NMDA) receptor mechanisms are seen to be involved
in the development of hyperalgesia, whether induced
*The term nonterminal is used so that it includes cancer patients with long
by opioid treatment or associated with neuropathic pain. The
survival who suffer chronic pain.
1246
© 2006 Southern Medical Association
Review Article
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Southern Medicat Journat • Volume 99, Number 11, November 2006
•a
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1247
Ballantytie • Opioids for Chronic Nonterminal Pain
NMDA receptor is also involved in the development of pharmacological opioid tolerance,'*°'''^ Repeated administration of
opioids results not only in the development of tolerance (a
desensitization process), but also leads to a pro-nociceptive
process (sensitization): thus pharmacological tolerance and
induced hyperalgesia are seen to coexist, just as analgesia and
hyperalgesia coexist,'"' The clinical quandary is obvious increasing doses could improve or worsen pain, A great deal
of uncertainty remains about whether opioid dose, length of
treatment or drug choice influences the development of hyperalgesia; and the exact clinical circumstances in which opioid-induced hyperalgesia interferes is also uncertain. Nevertheless, it has become clear that open-ended dose escalation
often fails to sustain analgesic efficacy, and the premise that
tolerance can always be overcome by dose escalation is now
questioned,^'' It is also clear that good analgesic efficacy is
not always sustained over time, and that there are clinical
situations in which pain and well being can be improved by
weaning rather than continuing opioid treatment.
provided a stable dose of opioid is used,"*" ''' This may not be
true when dosing is irregular or escalates,'*^
Side Effects and Complications
Opioid side effects are well known and include respiratory depression, nausea, sedation, euphoria or dysphoria, constipation and itching. With chronic use, most side effects
subside, since tolerance seems greater to side effects than to
analgesic effects. Constipation is an exception, and there appears to be no tolerance to the direct slowing effects of opioids on the bowel, so that constipation remains a high risk
and usually requires treatment. Although common side effects (except constipation), usually subside during chronic
treatment, they can sometimes interfere to the extent that
patients abandon the therapy,^* Respiratory depression is
rarely seen during chronic opioid therapy, but since this is a
potentially lethal side effect, one should remain vigilant. The
situation in which it most likely arises during chronic opioid
pain treatment is when the dose is rapidly escalated, dosing
errors occur, or when dmgs with unpredictable pharmacokinetics such as methadone are used, (Methadone's complexities are described under "Stmctured Opioid Therapy"). Other
Function and Quality of Life
Many medical practitiocomplications of opioid use are
more insidious, tend to be asners believe that improvements
Clinically,
testosterone
deficiency
is
the
sociated with long-term rather
in function and quality of life
most
frequent
hormonal
deficiency,
and
than
short-term use, and are
are needed for long-term opicomplex
and poorly understood.
oid treatment to be deemed a male patients can benefit from
These
include
hormonal and imsuccess, although a few believe testosterone replacement.
mune
effects,
and addiction.
that good pain relief, regardless of other markers of successful treatment, is enough to justify continued opioid treatHormonal and Immune Effects
ment. Despite the importance of this debate, the literature
Long-term opioid use results in clinically relevant supprovides surprisingly little evidence on nonanalgesia-related
pression
of both hypothalamopituitary-adrenal and -gonadal
outcomes. Some randomized trials combine assessments of
axes,
with
suppression in luteinizing hormone, follicle-stimpain relief with assessment of function, but the focus of these
ulating
hormone,
testosterone, estrogen and cortisol.^°~^^
assessments tends to vary with the primary interest of the
These
effects
have
been
demonstrated in addicts, past addicts
investigators,^''"''•'•'^''^ While some investigators demontreated
with
methadone
maintenance^"
and more recently, in
strate improvements in limited measures of function, others
opioid-treated
chronic
pain
patients.^'
The effects are most
find no difference (Table 1), Observational trials contribute
prominent in patients treated with intrathecal opioids,^•'"^^
little in the way of assessment of function. Although some
The gonadal effects can result in male and female infertility
report improvement in broad measures such as ability to perand in decreased libido, drive and aggression. Clinically,
form activities of daily living and retum to work, others do
testosterone deficiency is the most frequently manifest of
not comment. Few opioid trials measure quality of life, which
the deficiencies, and male patients can benefit from tesis again surprising given the importance of this factor and the
tosterone replacement.^'*'^'' Although the suppressive effact that there are several validated measurement instruments
fect of opioids on the endocrine system seems clear, deavailable.
termining the exact contribution to health of these effects
Several studies have looked specifically at cognitive
is not straightforward. Most chronic pain patients present
function, including the ability to drive and operate machinery
with complex medical and psychosocial histories, and
while on opioids. This question is obviously critical in terms
many have underlying neuroendocrine derangements, eiof whether opioid-treated patients should be encouraged to
ther because of coexisting medical illness, or because of
retum to work, to normal daily activities and in particular, to
the effects of their treatment. Thus, even knowing the likely
direct effects of opioids on endocrine function, their exact
driving. These studies find that cognitive function, manual
clinical relevance in an individual patient is not clear.
dexterity and reaction times are maintained at normal levels
1248
' 2006 Southern Medical Association
Review Article
Opioid drugs may affect immunity through their neuroendocrine effects, or through direct effects on the immune system.
Preclinical research has shown that opioids alter the development, differentiation and function of immune cells, and opioid
receptors have been demonstrated on immune cells.^^'^^ Evidence of immune modulation in humans is limited, hut opioids
have been shown to exacerhate immunosuppression in HIV patients, which suggests that prolonged opioid use may affect the
immune system, at least in immunocompromised persons.^^
There are no studies of immune function in patients receiving
long-term opioid therapy for chronic pain, but the direct evidence that opioids impair immune function in susceptible
individuals is concerning. Pain itself can suppress immune
function, so patients receiving prolonged opioid therapy without good pain relief are probably the most vulnerable.
ognized . . . that the efficacy of this therapy and its successful
management may relate as much to the quality of the personal
relationship between physician and patient as to the characteristics of the patient, drug, or dosing regime."^^ As is the
case with opioid maintenance for opioid addiction,^'*"^'' a
careful structured maintenance regimen is the best course for
preventing the emergence of problematic opioid-seeking behaviors. It follows that observed addiction rates are likely to
be higher when practice deviates from the careful controlled
approach recommended in published
Summary of Evidence Supporting
Long-term Opioid Use
Many years of clinical use of opioids for pain made it
clear that opioids are strong and effective analgesics. RanAddiction
domized trials confirm the sensitivity of several common
There is no doubt that the association of opioid use with
chronic pain conditions to opioids, and demonstrate that a
addiction produces many conflicts with regard to opioid treatshort course of treatment (up to 32 wk) using moderate doses
ment of pain. When it became necessary to introduce drug
(up to 180 mg morphine or equivalent) is effective.
regulations because the availability, use and abuse of opioids
With regard to sustained analgesic efficacy, many auand other addictive drugs had reached unacceptable levels,
thors report (in case reports and case series) prolonged and
this compounded the problem, adding a host of legal considsatisfactory analgesia for up to 6 years using moderate doses
erations to the existing moral
of opioid (up to 195 mg morand ethical dilemmas inherent in Opioid drugs may affect immunity
phine or equivalent). On the
balancing humane care with prothrough their neuroendocrine effects, or other hand, some investigators
tection from addiction. After the
report that failed patients imintroduction of regulations, it through direct effects on the immune
prove when taken off opioids.
took many years to reestablish system.
The suggestion that analgesic efopioid treatment as necessary
ficacy can always be mainand proper for the control of
tained, and tolerance reliably
acute and terminal cancer pain. In fact, as opioid use was
overcome by continued dose escalation must therefore be
reestablished for these indications, it became clear that prohquestioned. With regard to broader outcomes such as fiinction
lematic addiction virtually never arose during the treatment of
(ability to work and perform normal daily activity) and qualsevere, acute and cancer pain.^^'*° But long-term outpatient
ity oflife, which are considered the most important outcomes
opioid treatment is likely to he associated with higher risk.
of chronic opioid therapy by many clinicians, evidence is
Indeed, despite the somewhat optimistic picture painted by
limited.
early reports such as the seminal report by Portenoy and
Data on side effects suggest that common side effects
Foley estimating addiction risk during chronic opioid treatsuch as sedation and nausea usually resolve during chronic
ment at approximately 5%,^^ higher estimates of up to 19%
treatment, but a significant minority of patients will abandon
(this being the upper limit of addiction rates found in a sysopioid therapy because of side effects. More insidious liabiltematic review by Fishbain et al),^' are now accepted by the
ities include hormonal and immune effects and addiction.
medical community. There is a problem, however, with all
With regard to the hormonal effects, which are known to arise
estimates of addiction risk, and that is that iatrogenic opioid
in addicts and chronic pain patients, an important question is
addiction (addiction arising during opioid treatment of pain),
whether the effects, independent of other more direct opioid
is poorly defined and understood, despite years of effort to
effects, contribute to the general poor psychological and physclarify its terminology and processes.*^'*^ It seems that iatical health of opioid-treated patients. On the question of adrogenic opioid addiction is simply what the reporting person
diction and its prevalence during the treatment of pain with
says it is, and that the vast range of published estimates of
opioids, the literature is uncertain. While extremes of addicrisk refiects the lack of an agreed definition. Portenoy and
tion and freedom from addiction may seem clear, it remains
Foley understood at the outset that problematic addiction is
hard to determine whether the patients who fall between the
unlikely to arise when treatment is provided in a controlled,
extremes are addicted or not. There are no satisfactory deficarefiil and supportive setting. As they said: "It must be recnitions of iatrogenic opioid addiction, and the lack of an
Southern Medical Journal • Volume 99, Number 11, November 2006
1249
Baliantyne • Opioids for Chronic Nonterminal Pain
accepted incidence stems from this lack of agreed definition.
The published rate lies between 5% in some practice settings
and 19% in others, but as stated earlier, these figures can only
be interpreted as refiecting addiction as defined by the person
reporting - not by a generally agreed definition.
Table 2. Principles of chronic opioid therapy
• First try aggressive rehabilitative approach that may utilize opioids, but
aims to restore function and reduce reliance on medications
• Consider longer term treatment a serious undertaking that will require
the commitment of both physician and patient
• Ensure that other treatment options have been maximized
Structured Opioid Therapy
• Consider opioid therapy as an adjunct; sole opioid therapy is rarely
successfiil
Given the uncertainty that exists about the extent to
• Use goal-directed therapy; set limits and goals and agree to these
which iatrogenic opioid addiction arises, and which pa• Use of a written agreement, contract or consent is helpful for setting
tients will be affected, the concept of "universal precauout terms of treatment, terms for discontinuing treatment, and a clear
tions" applied to chronic opioid therapy has recently arisstatement of likely benefits and risks
en."^^ This approach suggests that since current
• Unless pain is occasional, base regimen on long-acting opioids, and
understanding precludes making reliable assessments of
avoid breakthrough medication
which patients are at risk of developing problematic ad• Ensure careful and regular follow up
diction, or indeed, which patients have already developed
• Monitoring of opioid use is helpful using pharmacy databases, pillcounting or urine toxicology
precursor tendencies toward addiction, the treatment should
•
Be prepared to wean and discontinue if treatment goals are not met
be applied in a uniformly careful and structured manner.
•
Maintain
good documentation
The following describes one such approach.
When a patient first presents with debilitating pain, early
aggressive treatment using a rehabilitative approach that aims
ment phase is entered. The pain diagnosis should be clearly
to restore fiinction and reduce reliance on medications is ofestablished and documented. Both parties should be satisfied
ten the best approach. Opioids can and should be used as
that
all other treatment options have been explored and do not
needed to facilitate this approach, preferably for a short time
provide adequate relief. Physionly. If this fails, and the phycians should carefully describe
sician and patient decide on a
If the physician and patient decide on the complications and risks of
long-term commitment to opia long-term commitment to opioid
long-term opioid therapy, explain
oid treatment, then the treatthe
monitoring policies of the
treatment,
then
the
treatment
should
ment should be goal-directed,
clinic
or practice, and allow paand carefully controlled. This be goal-directed and carefully
tients
to
express their anxieties. It
means selecting patients with controlled.
may
be
helpful
to have an explicit
the best chance of benefiting,
record of the patient's undercontinuously monitoring for
standing of the liabilities of longthe achievement of preset goals and onset of problematic
term treatment and the clinic's policies for monitoring, and
behavior, and maintaining the lowest effective dose to mainthis could be in the form of a signed written agreement or
tain analgesia and minimize complications. The principles of
consent. It is also helpful, at this stage, to establish and docstructured long-term opioid therapy are set out in Table 2.
ument the goals of treatment.
Selecting patients who are suitable for chronic opioid
After an initial titration to an effective dose, patients
therapy remains one of the greatest challenges surrounding
should ideally be maintained on a stable dose. In fact, the
the therapy, and there is little hard information to guide this
ability to maintain a stable dose is often an indication of
selection. Although there are well-established addiction cosuccessful treatment. For several reasons, including less likemorbidifies including depression, anxiety disorder, personallihood of developing euphoria and therefore addiction, less
ity disorder, history of physical or psychological trauma and
disruption of normal activity, and less likelihood of focusing
history of substance abuse, it is unclear whether patients in
on medication throughout the day, long-acting opioid prepacontrolled and consistent treatment programs are at risk of
rations administered round the clock are usually chosen when
developing problematic addiction. Present evidence suggests
treating long-term pain. The exact choice of opioid is less
that "at risk" patients do well in controlled programs, and
important, and for a detailed description of opioid drugs, the
should not be denied opioid treatment of pain solely on the
reader is referred to the standard texts. It is worth describing
basis of existing addiction comorbidities.*''"^'
some of the problems that arise during treatment with methThe commitment to long-term opioid therapy is a serious
one, and should be considered such by both patients and
physicians. Often, opioid therapy has already been started,
but this does not obviate the need for careful review of the
implications of long-term treatment once the long-term treat-
1250
adone. Since methadone has an intrinsically long half-life, it
can be used as a long-acting preparation. It does not need
pharmacological manipulation to extend its activity, therefore
it is cheap. It has often been recommended as a substitute for
long-acting morphine and oxycodone preparations, partly on
© 2006 Southern Medical Association
Review Article
the basis of price, and partly because of the problems that
status of the patient. The aim of each dose escalation is to
occurred when OxyContin became a popular drug of abuse.
reach a new, stable dose. For severe pain, it may be helpful to
However, methadone's metabolism, though prolonged, is
admit the patient to the hospital to help with diagnosis and
variable and idiosyncratic. This means that the degree to
rapid titration.
which the drug accumulates varies from patient to patient.
The use of very high doses of opioids is rarely helpful. It
Deaths due to respiratory depression have occurred because
is hard to say exactly what dose should be considered a high
ofthis unpredictability. Moreover, there can be serious interdose, and the issue of whether there is a clinical dose ceiling
actions, notably with antibiotics and antiflingals, as well as
is mueh debated. The traditional teaching is that an opioid
rare but dangerous prolongation of the QTc interval on the
dose can be increased in a limitless fashion, and that dose
electrocardiogram,^'^
increases are capable of overcoming pain. However, there are
several clinical situations in which continued dose escalation
During the stable phase of treatment, it is mandatory (by
does not seem to help, and patients complain of severe pain
law in most states) to provide prescriptions on a monthly
despite high-dose opioid therapy. For example, now that we
basis, and advisable to conduct comprehensive follow-up on
see very long survival in cancer patients, we also see cancer
a regular basis, assessing pain, the effect of pain on wellpain that gets out of control, and dose increases that do not
being, the achievement of treatment goals, level of function,
seem to help. This observation, together with the basic sciand quality of life. The patients' appearance in the clinic on
ence observation that there are multiple splice variants of
a monthly basis provides an opportunity to observe aberrant
endogenous opioid receptors resulting in much cross-sensibehaviors. Extra visits, requests for interim prescriptions and
tivity between various opioids, was the genesis ofthe clinical
frequent telephone calls to the clinic are considered warning
practice of opioid rotation,'"'^'* A switch to a different opioid
signs for addiction, although it is often impossible to detercan provide equal or better analgesia at half or less of the
mine whether these type of "nuisance" behaviors reflect desequivalent dose of the first opioid, and opioid rotation is a
peration with uncontrolled pain, fear of withdrawal associated with physical dependence,
reasonable way to control dose
or a chaotic lifestyle, rather
escalation. Purely on the basis
than addiction. Toxicology Extra visits, requests for interim
that the highest daily dose of opiscreening can be a helpful ad- prescriptions and frequent telephone
oid used in existing trials is 180
junct to monitoring for probmg morphine or morphine equivcalls to the clinic are considered
lematic opioid use, including
alent, this dose is suggested as
for addiction and diversion. warning signs for addiction.
the point one should begin to conSome practitioners believe that
sider dose reduction or opioid roall opioid-treated patients
tation. That is not to say that some
patients do not do well on higher daily doses, but rather, that
should be subjected to random urine screening. In support of
clinical experience suggests that the majority of patients do
this view, in one pain clinic, 43% of opioid-treated chronic
better if the daily dose is maintained below this level. One
nonterminal pain (CNTP) patients were judged "problemshould also consider that some liabilities, including neuroatic," and of these, 49% were identified using toxicology
toxicity, hyperalgesia, hormonal and immune effects and
screening, not behavioral parameters.^'' In some practice setproblematic behavior predominate when high doses are used.
tings, however, routine or random testing would seem unnecTo decide whether to maintain or terminate opioid treatessary.
ment, one must establish criteria for success and failure. These
Sometimes an increase in dose will be needed, but carecriteria tend to be subjective, and highly dependent on the
ful consideration should be given before each dose escalation.
treating physician's viewpoint. Pain relief that improves well
Tolerance to the analgesic effects of opioids can develop over
being, progress toward achieving treatment goals, improved
time, but the more common experience is that tolerance levels
function, and improved quality of life, are all reasonable criout, and most patients can be maintained at a stable dose.
teria for success and continuing therapy. Criteria for failure
Thus, if an increase in dose is needed, it should always alert
might include failure to reach any of the criteria for success,
the physician to the possibility that there are other reasons for
or deterioration in the cooperative relationship between phythe need for an increased dose. There may be a change in the
sician and patient.
patient's pain or underlying disease, which should be sought
and treated if necessary. The need for a higher dose may also
If the treatment fails, as determined by agreed criteria, it
be a manifestation of psychological need or addiction, which
should be weaned and discontinued. It is important to wean
should also be identified and treated if necessary. At high
cautiously to avoid unpleasant withdrawal, the experience of
doses, apparent tolerance may be a sign of opioid-induced
which can make it hard for the patient to give up the medihyperalgesia, which will be made worse by dose escalation.
cation a second time. Weaning can usually be accomplished
over 10 days, but the exact weaning schedule will depend on
Nevertheless, it is always reasonable to try a controlled
dose, drug and duration of treatment. If there is addiction.
dose escalation and see if this improves the pain and overall
Southern Medicat Journat • Volume 99, Number 11, November 2006
1251
Batlantyne • Opioids for Chronic Nonterminal Pain
discontinuation may not be the appropriate course of action,
but specialized treatment by a psychiatric or addictionist may
be needed. Many patients, especially those who are not doing
well on opioids, report an improvement in well being, and
possibly also in pain, after an opioid wean. If necessary,
opioid treatment can be restarted after a period of abstinence.
Opioid weaning is not always straightforward, and it is often
helpful to undergo the wean in a rehabilitation setting.
flicting directives, physicians face real patients, all presenting
with a cry for relief, all complex, and many whose decisionmaking capacity is compromised by the pervasive effect of
pain or the drugs used to treat pain. The challenge of balancing the needs and rights of patients, and the safety of patients
and community is enormous.
Future Directions
Early, when opioid treatment was extended to patients
with chronic pain, and the medical community was buoyed
Pain relief that improves well being, progress toward
by the success of opioid therapy for acute and cancer pain and
achieving treatment goals, improved function, and improved
the negligible addiction rates associated with these, there was
quality of life.
a great deal of confidence that the tenets of opioid treatment
for acute and cancer pain would apply equally to chronic
Failure
pain. Moreover, it was no longer acceptable to deny this
Failure to reach any of the criteria for success, or detetreatment to those in need, who now had an indisputable right
rioration in the cooperative relationship between physician
to be treated. Opioid prescribing for chronic pain increased
and patient.
exponentially during the last two decades of the twentieth
century,^" but so also did prescription drug abuse^''^^ and the
medical community's concern over addiction during opioid
Ethical Dilemmas
treatment of chronic pain. It was
Rapid changes in medical
realized that the pendulum had
science, technology and ftindswung too far and indeed, opioid
ing during the past century The surest way to hurt patients (and
prescribing and prescription drug
have had a profound effect on society) is to abandon them when
abuse have leveled off since the
the role of physicians in soci- they deviate from the constructive
year 2000. Despite the cost, the
ety and their relationship with
relationship envisaged by the treating
lessons learned from this experipatients. Physicians are propractitioner, only to trail from
ence have been invaluable. It is
vided with tools that can alter
now understood that opioid effilife itself, so patients are no physician to physician to obtain the
drug
they
need,
or
worse
still,
seek
cacy
can diminish over time, and
longer content to put medical
that
open-ended
dose escalation
decisions solely in the hands of illicit supplies.
does not always overcome apparphysicians. The Hippocratic
ent tolerance. It has become clear
tradition of benevolent paterhow little is understood about the complex relationship benalism, protecting patients through an ethical code "productween pain, analgesia and addiction, and this has prompted
ing good for the patient and protecting that patient from
the adoption of structured management protocols that aim to
harm,"^^ has been replaced by a guidance-cooperation model
minimize addiction. Concerns about efficacy and addiction
where the physician steers the patient, but the patient is the
have prompted an urgent search to discover more about the
primary decision maker. Increasingly, moral and ethical debasic mechanisms of opioid analgesia, tolerance, dependence
cisions are removed from the confmes of individual physiand addiction. Insidious opioid complications, such as horcian-patient relationships, and move into the realm of public
monal suppression, that potentially worsen pain's disability,
morality. As part of this trend, medical practice is directed
have emerged as a valid additional reason for keeping doses
more by guidelines, laws and mandates, and less by the dicwithin a moderate range. But perhaps the greatest lesson is
tates of individual physicians. Patients' right to direct their
that it does not help to deny the addiction risk, or to fragment
own treatment is expressed in the Patients Bill of Rights,^*
pain and addiction care. Remembering that opioid maintenance
and their right to pain and opioid treatment expressed in
treatment for opioid addiction has shown remarkable success in
"intractable pain" statutes.^' Physicians are encouraged to
keeping addiction under control and allowing afflicted individprovide pain and opioid treatment by Federal Agencies,^^
uals to lead near normal lives,^"^*'^'' careful structured opioid
State Medical Boards''^ and credentialing bodies.''^ But they
treatment of pain is the best way known to protect opioidare also constrained by legal barriers that tend to inhibit pretreated pain patients from becoming addicted. The surest way
scribing, and that compound the moral and ethical dilemmas
to hurt them (and society) is to abandon them when they
that are inherent in the provision of opioids because of their
deviate from the constructive relationship envisaged by the
indispensable role in pain management pitched against their
treating practitioner, only to trail from physician to physician
tendency to produce addiction. Against a background of con-
Success
1252
© 2006 Southern Medical Association
Review Article
to obtain the drug they need, or worse still, seek illieit supplies. There is still a lot to be learned about basic opioid
mechanisms, and about how to predict success and avoid
disaster. Several groups are in the process of developing tools
to help identify and predict risk, and these efforts are likely to
help physicians who are currently tom between their duty to
patients, the community and the law, with little guidance to
help them.^'*~^^ In the meantime, existing evidence strongly
suggests that the best way to help patients needing opioid
treatment for chronic pain is to provide the treatment in a
cautious, selective and supportive manner.
16. Huse E, Larbig W, Flor H, et al. The effect of opioids on phantom limb
pain and cortical reorganization. Pain 2001;90:47-55.
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I
Begin challenging your own assumptions. Your assumptions are your windows on the world. Scrub them off
every once in awhile, or the light won't come in.
—Alan Aida
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