| Nonopioid
analgesics* The International Association for
the Study of Pain defines pain as an unpleasant sensory
and emotional experience associated with tissue damage or
described in terms of such damage. This definition
clearly includes pain states not associated with tissue
damage, such as headache and phantom pain. These and
other chronic pain conditions have been treated with
nonopioid analgesics, such as anticonvulsants and
antidepressants.
In 1990, the World Health Organization proposed an
analgesic ladder for the treatment of cancer pain. The
first step of the ladder calls for the use of
acetaminophen or nonsteroidal anti-inflammatory drugs
with or without an adjuvant medication. The second step
suggests a weak opioid analgesic with or without
adjuvants, and the third step suggests a strong opioid
analgesic with or without adjuvant drugs. The use of this
analgesic ladder has been extrapolated to noncancer pain
states, but little is known regarding the efficacy of
combinations of analgesics, antidepressants, or
anticonvulsants.
This report summarizes some data on the efficacy of
nonopioid analgesics in various pain syndromes.
POSTHERPETIC NEURALGIA
Postherpetic neuralgia is one pain syndrome that has
been well studied. An average dose of 73 mg per day of
amitriptyline produced improvement in 16 of 24 patients
as opposed to placebo response in 1 of 24 patients (1).
The number of treated patients needed to produce 50% pain
relief in 1 patient was 1.6. The number needed to treat
for major harm was 24. Desipramine, at an average dose of
167 mg per day, produced a response in 12 of 19 patients
as opposed to 2 of 19 patients on placebo (2). The number
needed to treat for a 50% response was 1.9. The number
needed to treat for major harm was 13. Gabapentin, in a
dose range of 1200 to 3600 mg a day, produced a response
in 47 of 109 patients vs a placebo response in 14 of 116
patients (3). The number needed to treat for 50%
improvement was 3.2.
Oxycodone, in doses of 20 to 60 mg per day, produced
improvement in 22 of 38 patients, as opposed to 7 of 38
patients on placebo. The number needed to treat was 2.5.
Thus, nonopioid analgesic drugs produce a number
needed to treat in a range comparable to that of
oxycodone in the dose range described.
DIABETIC NEUROPATHY
Diabetic neuropathy has been shown to respond to a
number of tricyclic antidepressants. Amitriptyline, at an
average dose of 90 mg a day, produced a response in 15 of
29 patients vs 1 of 29 patients on placebo (4). The
number needed to treat for 50% relief was 2.1. The number
needed to treat for minor harm was 9.7. In another study,
amitriptyline and desipramine showed similar results, but
paroxetine was no better than placebo in
nondepressed patients (5). Gabapentin, at an average
dose of 3600 mg a day, produced a response in 47 of 79
patients vs 25 of 76 patients on placebo (6).
Carbamazepine, in a dose range of 200 to 600 mg per
day, produced response in 28 of 30 patients, as opposed
to 19 of 30 patients on placebo. The number needed to
treat was 3.3. Dextromethorphan, in an average dose
of 381 mg per day, produced response in 7 of 13 patients,
as opposed to 0 of 13 patients on placebo, with a number
needed to treat of 1.9. Tramadol, in a dose range of 100
to 400 mg per day, produced response in 43 of 63 patients
compared with 23 of 64 patients on placebo, with a number
needed to treat of 3.4. Madopar, in a dose of 300 mg per
day, produced a response in 8 of 14 patients compared
with 3 of 11 on placebo, with a number needed to treat of
3.4.
TRIGEMINAL NEURALGIA
Carbamazepine, in doses of 400 to 800 mg per day,
produced response in 144 of 268 patients compared with 35
of 190 patients on placebo, with a number needed to treat
of 2.6. Lamotrigine, in an average dose of 400 mg per
day, produced a response in 7 of 13 patients compared
with 1 of 14 patients on placebo, with a number needed to
treat of 2.1. Baclofen, in a dose range of 60 to 80 mg
per day, produced a response in 8 of 10 patients compared
with 1 of 10 patients on placebo, with a number needed to
treat of 1.4.
POLYNEUROPATHY
Polyneuropathy pain has been treated with 240 mg
tramadol, with a number needed to treat of 4.3.
CHRONIC LOW BACK PAIN
Maprotiline, at doses of 150 mg per day, produced a
40% reduction in low back pain compared with 26% with
paroxetine and 27% with placebo. Patients with low back
pain treated with oxycodone and sustained-released
morphine experienced an approximate 40% reduction in pain
compared with patients taking nonsteroidal
anti-inflammatory drugs.
No head-to-head comparisons of opioid vs nonopioid
analgesics have been reported. However, the magnitude of
response with nonopioid analgesics may be in the same
range as the response to opioid analgesics.
SIDE EFFECTS
The quest for better pain control is a good one;
however, one study has shown that the death rate from
drug interactions has increased significantly over the
past decade. Analgesics and other centrally acting
medications are responsible for most of the increase (7).
Additionally, concerns about opioid dependency will
continue to drive nonopioid analgesic prescribing. While
opioid addiction is probably uncommon in a primary care
setting, one study showed an approximate 25% incidence of
abuse in a pain clinic setting (8). Investigators
required 3 of 5 clinical criteria to make the diagnosis:
- Patient concern with opiates during the clinic
visits to the point that it interferes with other
issues relating to pain management and persists
beyond the third treatment visit.
- Three or more early refills and escalating drug
use in the absence of acute changes in clinical
status.
- Frequent phone calls to the clinic for early
refills or a single instance in which the patient
causes a disturbance with the office staff.
- A pattern of problems with prescriptions, such as
loss, stolen, or spilled medication.
- Supplemental sources of opioids—other legal
providers, emergency rooms, or illegal providers.
Toxicity and side effects are real concerns despite
the enthusiasm for better pain control. Numbers needed to
treat for harm range from 2 to 30. While there are little
data guiding clinicians prescribing multiple analgesic
drugs, clinicians generally avoid adding more than one
drug at a time; educate patients regarding the limited
efficacy of pharmacologic treatments, whether they are
opioid or nonopioid; and educate patients regarding the
time course of response during dose-escalation periods
for antidepressants and anticonvulsants.
—Carl Noe, MD
- Watson CP, Evans RJ, Reed K,
Merskey H, Goldsmith L, Warsh J.
Amitriptyline versus placebo in postherpetic
neuralgia. Neurology
1982;32:671–673.
- Kishore-Kumar R, Max MB,
Schafer SC, Gaughan AM, Smoller B, Gracely
RH, Dubner R. Desipramine relieves
postherpetic neuralgia. Clin Pharmacol
Ther 1990;47:305–312.
- Rowbotham M, Harden N, Stacey
B, Bernstein P, Magnus-Miller L.
Gabapentin for the treatment of
postherpetic neuralgia: a randomized
controlled trial. JAMA
1998;280:1837–1842.
- Max MB, Culnane M, Schafer SC,
Gracely RH, Walther DJ, Smoller B, Dubner R.
Amitriptyline relieves diabetic neuropathy
pain in patients with normal or depressed
mood. Neurology 1987;37:589–596.
- Max MB, Lynch SA, Muir J,
Shoaf SE, Smoller B, Dubner R. Effects of
desipramine, amitriptyline, and fluoxetine on
pain in diabetic neuropathy. N Engl J Med
1992;326:1250–1256.
- Backonja M, Beydoun A, Edwards
KR, Schwartz SL, Fonseca V, Hes M, LaMoreaux
L, Garofalo E. Gabapentin for the symptomatic
treatment of painful neuropathy in patients
with diabetes mellitus: a randomized
controlled trial. JAMA
1998;280:1831–1836.
- Phillips DP, Christenfeld N,
Glynn LM. Increase in US medication-error
deaths between 1983 and 1993. Lancet
1998;351:643–644.
- Chabal C, Erjavec MK, Jacobson
L, Mariano A, Chaney E. Prescription opiate
abuse in chronic pain patients: clinical
criteria, incidence, and predictors. Clin
J Pain 1997;13:150–155.
Opioid therapy in chronic pain
management
While the use of opioid therapy in patients who have
acute postoperative pain is very well accepted, its use
in patients who have chronic nonmalignant pain is
generally less accepted. The importance of treating
patients who have chronic pain is underscored by the
economic impact of chronic pain in the USA. More than 20
million employees miss 433 million work days due to pain,
and indirect business costs have been estimated to be $45
billion. The health care cost due to chronic pain has
been estimated at $885 billion. In a recent study that
surveyed 1.2 million adults, 1 of 5 related that they had
some form of chronic pain. Among those with chronic pain,
approximately 40% reported that the pain had a
“major” impact on their lives, with half of
those noting that they get depressed. This further
reinforces the prevalence of the pain problem in our
society.
Where do opioids fit in pain treatment? While the goal
of medicine is the eradication of disease, this is not
always possible for patients who have chronic pain.
Beyond that goal, medicine should seek to relieve
symptoms and improve pain and suffering, thus enabling
patients to improve or maintain functional status with
medication, education, and counseling. This article
focuses on the use of opioid therapy in chronic pain,
reviewing the classification and mechanism of action of
opiates, the assessment and treatment of patients with
these drugs, and relevant research studies.
CLASSIFICATION AND MECHANISM OF ACTION
Opioids can be classified into several different
categories. One system divides them into naturally
occurring opioid analogues, semisynthetic derivatives,
and totally synthetic opioids. The most commonly used
medications are the semisynthetics and the fully
synthetic opioid medications. The semisynthetics are
derived from the modification of the morphine molecule.
Opioids work at many different receptors, including
the 5 opioid receptors: mu, kappa, sigma, delta, and
epsilon. Opioids work at the supraspinal and spinal
levels and outside the central nervous system. When
opioids attach to receptors at the spinal level or in the
peripheral nervous system, they modify the transmission
of painful signals, diminishing pain perception. Each
opioid may act at several receptors. At the supraspinal
level, opioid receptors send descending inhibitory
signals that modify incoming pain signals at the synaptic
spinal level. In addition to inhibiting painful signal
transmission, opioids work in the limbic system, which
alters emotional response to pain. Each opioid has
different affinities for different receptors, so patients
may have different responses to different opioids.
PATIENT ASSESSMENT AND TREATMENT
It is important to evaluate every patient before
initiating narcotic therapy. This includes taking a
complete history and conducting a physical examination,
noting the characteristics of the patient's pain;
evaluating the patient's psychological state and social
situation; conducting a complete neurological exam;
reviewing radiologic and laboratory diagnostic tests; and
evaluating all therapeutic modalities. Once a thorough
evaluation has been performed, the clinician should
develop a pain treatment continuum for the patient,
starting with over-the-counter analgesic drugs and
progressing to other coanalgesics, opioid medications,
and more invasive modalities. The World Health
Organization 3-Step Ladder is an excellent model. It
suggests beginning with a nonopioid medication, adding a
weaker opioid and an adjuvant if the first step is
insufficient, and incorporating a longer acting, more
potent opioid analgesic if pain relief remains
insufficient.
When incorporating a weak opioid analgesic, the
clinician must consider that most of these products are
associated with acetaminophen and some are associated
with aspirin, thus limiting the dosages of medications
that a patient can receive. Different sources have
different recommendations regarding maximum acetaminophen
exposure for a normal adult. The recommended daily dose
ranges from 21/2 grams per day to 4 grams per day. In
patients with chronic acetaminophen exposure due to
chronic pain, I traditionally limit the dose to 21/2
grams per day. Based on the more commonly used
fixed-combination opioid analgesics, that translates to 4
to 5 tablets per day. The weaker analgesics are
traditionally considered products such as hydrocodone,
short-acting oxycodone, and codeine. When inadequate
relief is obtained with them, the clinician may prescribe
a longer acting opioid analgesic, such as
sustained-release morphine, sustained-release oxycodone,
methadone, or a transdermal fentanyl system. Each product
has potential benefits; the clinician should choose the
one best tailored to the patient's needs.
One thing to consider is the side effects that can be
associated with these medications. With time, most side
effects related to opioids will improve or resolve,
except for constipation. When initiating patients on
chronic opioid therapy, the clinician should review with
them his or her expectations regarding compliance,
refills, and the importance of consuming the medications
as prescribed.
RESEARCH ON OPIATES
To date, there are very few well-controlled,
double-blinded studies that indicate the effectiveness of
chronic opioid therapy in nonmalignant pain. One recent
1-year study compared anti-inflammatory medications with
2 doses of opioid therapy in patients who had chronic
back pain (1). The objective of the study was to
determine the safety and efficacy of narcotics in
patients who had chronic pain. The results suggest that
opioid therapy has a positive effect on pain and mood but
little effect on activity and sleep. As opioid therapy
was tapered off, no long-term benefit was noted; patients
returned to their baseline pain levels.
In another study, sustained-release oxycodone was
compared with placebo in patients who had postherpetic
neuralgia (2). This was a randomized crossover study:
patients in both groups were on sustained-release
oxycodone at one point and placebo at another point.
Significant improvement was noted in the pain intensity
of patients taking the controlled-release oxycodone; both
steady pain and allodynia pains were significantly better
than in the placebo group. This study further solidifies
the argument that chronic opioids can be effective in
treating neuropathic pain as well as somatic pain.
Incorporating opioid analgesics in the treatment of
chronic nonmalignant pain is effective in the appropriate
patient population. It's important to move beyond
prescribing opioids for chronic pain and to encourage a
comprehensive, interdisciplinary approach to improve
patient outcomes.
—Richard L. Vera, MD
- Jamison RN, Raymond SA,
Slawsby EA, Nedeljkovic SS, Katz NP. Opioid
therapy for chronic noncancer back pain. A
randomized prospective study. Spine
1998;23:2591–2600.
- Watson CP, Babul N. Efficacy
of oxycodone in neuropathic pain: a
randomized trial in postherpetic neuralgia. Neurology
1998;50:1837–1841.
Interventional pain management
In approaching pain treatment, a continuum of
therapies is available, ranging from simple to complex.
It is important to first establish a diagnosis and
therapy goals. Initial therapy may consist of oral
medication, active physical rehabilitation, psychological
therapy, or some combination of all 3 modalities.
At some point, interventional management may be
indicated. This approach may be used for diagnostic or
therapeutic reasons. Diagnostic blocks may help establish
or rule out a diagnosis. They can also aid in localizing
pathology, such as a selective nerve root block in a
patient with radicular pain. Therapeutic intervention, on
the other hand, can be used to decrease pain levels to
help potentiate rehabilitation efforts or to permanently
decrease or eliminate pain, as is achieved with implant
therapy. Pain therapy outcomes can be measured by
assessing reduction in pain levels, reduction in
analgesic consumption, enhancement of activities of daily
living, return to work, and improvement of other
functional abilities.
Although some simple procedures, such as trigger point
injections, may be done in the examination room, most are
performed in the outpatient area. For more uncomfortable
procedures or for patients requiring sedation, a
peripheral intravenous line may be placed before
sedation. Patients' vital signs are recorded with
standard monitors. In the preoperative area, nurses
screen patients for pertinent information, such as drug
allergies or specific concerns. Contraindications to
injections include local infection, coagulopathy, history
of untoward reaction to steroids, symptoms and signs
indicating cauda equina syndrome, and idiopathic or
clearly psychogenic pain. After the procedure, the
patient is monitored for 20 to 30 minutes before being
discharged home.
This paper discusses a number of interventional
therapies available: simple blocks, cryoneurolysis,
radiofrequency thermocoagulation, neurolytic blocks, and
implantation therapy. It closes with a discussion of
potential developments in the field.
SIMPLE BLOCKS
Examples of simple blocks include intercostal blocks,
ilioinguinal blocks, occipital nerve blocks, brachial
plexus blocks, and stellate ganglion blocks. Many
injections require the use of fluoroscopy. Examples
include epidural steroid injections, nerve root blocks,
facet blocks, and sympathetic blocks. With fluoroscopy,
the doctor can easily visualize and target or avoid the
spinal column and other landmarks. The anatomy of the
spine varies not only according to the level (cervical,
thoracic, lumbar, sacral) but also among individuals.
Injecting a 30-year-old person with a herniated disc can
be very different from injecting an elderly patient with
severe scoliosis. The use of fluoroscopy has proven very
important in making injections safe, efficient, and
effective. The use of fluoroscopy mandates protective
leaded gear. At times, epidural catheters may be
indicated, either for aid in injecting substances to more
specific target areas or for even, prolonged infusion for
pain control.
CRYONEUROLYSIS
Cryoneurolysis is the freezing of a peripheral nerve
to obtain analgesia. This is performed with the use of a
cryoprobe connected to a cryoneurolysis machine that also
allows for nerve stimulation to help target the nerve.
Once the probe is in place, a small ice ball forms at the
tip. This provides an analgesic effect that lasts for
weeks to months without damaging the frozen structures.
Nerves that respond well to freezing include the
ilioinguinal nerves, intercostal nerves, and occipital
nerves.
RADIOFREQUENCY THERMOCOAGULATION
Radiofrequency thermocoagulation, on the other hand,
is the “burning” of nerves. It actually refers
to the passage of current from an electrode placed in
nervous tissue that heats and destroys the tissue around
the electrode. Because radiofrequency current heats the
tissue and the tissue heats the electrode tip, burning is
not a correct description of the procedure. Temperature
is the basic parameter and should be measured.
Sympathetic nerves and some other small somatic nerves,
such as those that innervate the facet joints, respond
very well to this modality.
NEUROLYTIC BLOCKS
Neurolytic blocks are performed by injecting a
substance such as phenol or alcohol into specific nerves.
Because these procedures are destructive and
irreversible, they are usually reserved for patients with
intractable pain that hasn't responded to more simple
techniques. The most common example would be a celiac
plexus block for pancreatic cancer.
IMPLANTATION THERAPY
Implantation therapy for chronic intractable pain is
an effective alternative to neuroablation or even
reoperation. Implantation therapy consists of
neuromodulation and intrathecal infusion.
Neuromodulation is achieved by placing stimulating
electrodes into the epidural space. It works on the
principle of the gate-control theory of
pain—stimulation of large-diameter afferents in the
dorsal column. Initially, appropriate candidates undergo
percutaneous placement of the electrodes as a trial.
Depending on what level on the spine the lead is placed,
the practitioner can treat pain from the occipital level
down to the foot. If the patient feels a
“buzzing” sensation throughout the area of
pain, he or she may go on to implantation. This entails
connecting either a single or dual lead to a generator
battery placed under the skin. The entire system is
subcutaneous.
Intrathecal therapy involves placing a small catheter
into the subarachnoid space for direct delivery of
analgesic substances to the cerebrospinal fluid.
Placement of a drug via this route, such as morphine for
pain or baclofen for spasticity, allows for direct
binding to receptors at the spinal cord. Small amounts of
drug can be delivered effectively, decreasing the number
of side effects. This outpatient procedure entails the
subcutaneous implantation of a programmable pump
connected to a tunneled catheter that is percutaneously
placed intrathecally. Prior to implantation, a trial
injection or infusion of medication is performed to
assess effectiveness and side effects. Because the pump
can hold only a certain volume of medication, refills are
required every 1 to 3 months. A trained nurse can provide
the refills on an outpatient basis.
DEVELOPMENTS IN INTERVENTIONAL THERAPY
Developments in interventional therapy involve new
techniques, new medications, and new technologies. A new
“pulse wave” radiofrequency device is available
that may provide analgesia without actual nerve
destruction. Researchers are trying to enable the
injection of substances to inhibit the formation of scar
tissue at the spinal level. Efficient myeloscopes for
visualization of the epidural space are still being
perfected.
—Tibor A. Racz, MD
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